JP2016193870A - Therapeutic agent for chronic myelogenous leukemia - Google Patents
Therapeutic agent for chronic myelogenous leukemia Download PDFInfo
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- JP2016193870A JP2016193870A JP2015075195A JP2015075195A JP2016193870A JP 2016193870 A JP2016193870 A JP 2016193870A JP 2015075195 A JP2015075195 A JP 2015075195A JP 2015075195 A JP2015075195 A JP 2015075195A JP 2016193870 A JP2016193870 A JP 2016193870A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
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Abstract
Description
本発明は、慢性骨髄性白血病(以下、「CML」ともいう。)治療剤に関する。より詳細には、本発明は、p38MAPK(以下、「p38」ともいう。)阻害薬を含有してなるCML治療剤、特にCML幹細胞除去剤、チロシンキナーゼ阻害薬(以下、「TKI」ともいう。)抵抗性抑制剤およびマルチキナーゼ阻害薬抵抗性抑制剤;並びに、p38阻害薬をTKIまたはマルチキナーゼ阻害薬と組み合わせてなるCML治療剤、特に、再発CML治療剤、CMLとフィラデルフィア染色体陽性急性リンパ性白血病(以下、「Ph+ALL」ともいう)の再発予防剤に関する。 The present invention relates to a therapeutic agent for chronic myelogenous leukemia (hereinafter also referred to as “CML”). More specifically, the present invention is also referred to as a CML therapeutic agent containing a p38MAPK (hereinafter also referred to as “p38”) inhibitor, particularly a CML stem cell removing agent, a tyrosine kinase inhibitor (hereinafter also referred to as “TKI”). ) Resistance inhibitors and multikinase inhibitors Resistance inhibitors; and CML treatments combining p38 inhibitors with TKI or multikinase inhibitors, especially recurrent CML treatments, CML and Philadelphia chromosome positive acute lymph The present invention relates to a prophylactic agent for recurrent leukemia (hereinafter also referred to as “Ph + ALL”).
慢性骨髄性白血病(CML)は、造血幹細胞を発症起源とする骨髄増殖性疾患であり、数年の慢性期の後、移行期を経て重篤な病態を呈する急性転化期へと進行する。CMLの治療においては、慢性期に徹底した治療を行って急性転化期への移行を防ぐことが重要となる。CML患者ではフィラデルフィア染色体とよばれる染色体転座t(9;22)(q34;q22)がみられ、この転座により、恒常的に活性化されたチロシンキナーゼBCR-ABL融合蛋白質を発現することが、CMLの発症の原因として知られている。BCR-ABLチロシンキナーゼは細胞内基質や自己をリン酸化し、細胞増殖、形質転換、アポトーシス抑制に関わる様々な細胞内シグナル伝達を活性化することにより、CML発症に深く関与する。 Chronic myelogenous leukemia (CML) is a myeloproliferative disease whose origin originates from hematopoietic stem cells, and progresses from a chronic phase for several years to an acute transition phase that exhibits a serious pathological condition through a transitional phase. In the treatment of CML, it is important that thorough treatment is performed in the chronic phase to prevent transition to the acute phase. CML patients have a chromosomal translocation t (9; 22) (q34; q22) called the Philadelphia chromosome, and this translocation expresses a constitutively activated tyrosine kinase BCR-ABL fusion protein However, it is known as the cause of the development of CML. BCR-ABL tyrosine kinase is deeply involved in the development of CML by phosphorylating intracellular substrates and self, and activating various intracellular signaling related to cell proliferation, transformation, and apoptosis suppression.
CMLの治療薬としてABLに対するチロシンキナーゼ阻害薬(TKI)イマチニブ(上市薬はメシル酸塩)が開発され、CML患者の治療成績を著しく改善した。イマチニブは、チロシンキナーゼのATP結合部位に競合的に結合し、基質リン酸化に続くシグナル伝達を阻害することにより、細胞増殖を抑制し、アポトーシスを誘導してCML細胞を選択的に傷害する。このイマチニブや、さらに治療効果の高い、第二世代TKIのニロチニブ、ダサチニブ、ボスチニブ、ラドチニブ(IY5511)がCML患者の治療に用いられている。
しかし、イマチニブなどのTKI治療後のCML患者において、TKIが効かなくなったCML(治療抵抗性の再発CML)が臨床上の重大な問題となっている。近年、この再発のメカニズムとして、T315I(イマチニブ結合部位である315番目のスレオニン残基がイソロイシンに置換されている)に代表されるTKI抵抗性のBCR-ABLの点突然変異が出現することが明らかとなった。TKI耐性BCR-ABL1を発現するCML患者の治療薬として、マルチキナーゼ阻害薬ポナチニブが開発され、米国及びEUにおいて、前治療のTKIに抵抗性又は不耐容となったCMLを対象に承認されている。しかし、TKI抵抗性CML細胞の増殖源となるCML幹細胞を完全には排除できないため、ポナチニブ治療を中止すると再発の懸念がある。そのため、患者はポナチニブ治療を継続し続けなければならなくなる。また、TKI抵抗性CML幹細胞を発生起源として、さらに複数の遺伝子変異(コンパウンド変異)を持つCML幹細胞が発生すると、さらなるポナチニブ抵抗性を引き起こす原因ともなる。したがって、CMLを根治するためには、CML幹細胞を根絶する治療方法の開発が必要である。
A tyrosine kinase inhibitor (TKI) imatinib (marketed drug is mesylate) for ABL has been developed as a treatment for CML, which has significantly improved the outcome of CML patients. Imatinib competitively binds to the ATP binding site of tyrosine kinase and inhibits signal transduction following substrate phosphorylation, thereby suppressing cell proliferation and inducing apoptosis to selectively damage CML cells. Imatinib and the second-generation TKIs nilotinib, dasatinib, bosutinib, and radotinib (IY5511), which are more effective, are used to treat CML patients.
However, in patients with CML after TKI treatment such as imatinib, CML (treatment-resistant recurrent CML) in which TKI has become ineffective has become a serious clinical problem. Recently, as a mechanism of this recurrence, TKI-resistant point mutation of BCR-ABL represented by T315I (imatinib binding site 315th threonine residue is replaced with isoleucine) appears. It became. The multikinase inhibitor ponatinib has been developed as a treatment for CML patients expressing TKI-resistant BCR-ABL1, and has been approved in the US and EU for CML that has become resistant or intolerant to the previous treatment TKI . However, CML stem cells, which are the source of proliferation of TKI-resistant CML cells, cannot be completely eliminated, and there is a concern of recurrence when ponatinib treatment is discontinued. As a result, the patient must continue to take ponatinib therapy. In addition, when CML stem cells having a plurality of gene mutations (compound mutations) are generated from TKI-resistant CML stem cells as a developmental origin, it may cause further ponatinib resistance. Therefore, in order to cure CML, it is necessary to develop a therapeutic method for eradicating CML stem cells.
CML幹細胞を抑制するいくつかの薬剤が報告され、TKIとの併用によるCML治療が提案されている。例えば、本発明者は以前、TGF-β-FOXOシグナル(特許文献1)やTGF-β-Smadシグナル(特許文献2)を阻害することにより、CML幹細胞を効率よく除去することができ、TKI抵抗性を抑制し得ること、さらにTKIとの併用により、分化したCML細胞とCML幹細胞とを同時に排除し得ることを見出し、寛解後の再発やTKI抵抗性獲得のリスクの低減された新規なCMLの治療手段を開発した。 Several drugs that suppress CML stem cells have been reported, and CML therapy in combination with TKI has been proposed. For example, the present inventor has previously been able to efficiently remove CML stem cells by inhibiting the TGF-β-FOXO signal (Patent Document 1) and the TGF-β-Smad signal (Patent Document 2). New CML with reduced risk of relapse after remission and acquisition of TKI resistance. Therapeutic means were developed.
ところで、p38 MAPK(mitogen-activated protein kinase)シグナル伝達経路は、環境ストレスや紫外線、アポトーシス、炎症反応に関与することが知られている。また、近年、種々のがんにおいてp38の活性化が報告され(非特許文献1)、p38の選択的阻害剤LY2228820が複数のがんモデル(黒色腫、非小細胞肺癌、卵巣癌、神経膠腫、骨髄腫、乳癌)で腫瘍の増殖を遅延させたとの報告もある(非特許文献2)。しかし、がんにおけるp38の作用は、腫瘍とその微小環境との相互作用と深く関わっており、がん種によって大きく異なると考えられている。特にCMLとの関連では、p38の活性化はCML細胞にアポトーシスを誘導し(非特許文献3、4)、CML細胞株K562細胞においてp38を阻害するとアポトーシスが抑制される(非特許文献5、6)ことが報告されている。また、ダサチニブの白血病治療効果にはp38の活性化が必須であるとの報告もある(非特許文献7)。 By the way, it is known that the p38 MAPK (mitogen-activated protein kinase) signal transduction pathway is involved in environmental stress, ultraviolet light, apoptosis, and inflammatory reaction. In recent years, activation of p38 has been reported in various cancers (Non-patent Document 1), and a selective inhibitor of p38, LY2228820, has been developed in several cancer models (melanoma, non-small cell lung cancer, ovarian cancer, glia). There is also a report that the growth of the tumor was delayed in the tumor (myeloma, breast cancer) (non-patent document 2). However, the action of p38 in cancer is closely related to the interaction between the tumor and its microenvironment, and is thought to vary greatly depending on the cancer type. In particular, in the context of CML, p38 activation induces apoptosis in CML cells (Non-Patent Documents 3 and 4), and inhibition of p38 in CML cell line K562 cells suppresses apoptosis (Non-Patent Documents 5 and 6). ) Has been reported. There is also a report that activation of p38 is essential for the therapeutic effect of dasatinib on leukemia (Non-patent Document 7).
本発明の目的は、CML幹細胞の維持に関与する新規シグナル伝達経路を明らかにし、当該シグナルを選択的に阻害することにより安全かつ有効なCML幹細胞除去薬、TKI抵抗性抑制薬を提供することである。また、TKI等との併用により、分化したCML細胞とCML幹細胞とを同時に排除し得る、寛解後の再発やTKI抵抗性獲得のリスクの低減されたCMLの治療手段を提供することである。また、T315Iに代表されるTKIが効かなくなった変異型BCR-ABLを発現するCML患者に対して、第三世代マルチキナーゼ阻害薬とCML幹細胞除去薬を併用することで、CML及びPh+ALLの再発予防並びに治療手段を提供することである。 An object of the present invention is to clarify a novel signal transduction pathway involved in maintenance of CML stem cells, and to provide a safe and effective CML stem cell removal agent and TKI resistance inhibitor by selectively inhibiting the signal. is there. Another object of the present invention is to provide a treatment method for CML with reduced risk of recurrence after remission and acquisition of TKI resistance, which can simultaneously eliminate differentiated CML cells and CML stem cells in combination with TKI or the like. In addition, for CML patients expressing mutant BCR-ABL in which TKI typified by T315I has become ineffective, CML and Ph + ALL of CML and Ph + ALL can be obtained by using a combination of a third-generation multikinase inhibitor and a CML stem cell depleting agent. To provide a means of preventing and treating recurrence.
本発明者は、上記の目的を達成すべく鋭意検討を重ねる中で、CML幹細胞においてp38シグナル伝達経路が顕著に活性化されていることを見出した。そこで、本発明者は、p38阻害の効果を調べるため、種々のp38の選択的阻害薬の存在下で、マウスCML幹細胞をフィーダー細胞と共培養した(この共培養は、インビボでのがん微小環境を模倣する)。その結果、いずれのp38阻害薬もマウスCML幹細胞の増殖を抑制した。 The present inventor has found that the p38 signaling pathway is remarkably activated in CML stem cells in the intensive study to achieve the above object. Therefore, the present inventor co-cultured mouse CML stem cells with feeder cells in the presence of various selective inhibitors of p38 in order to examine the effect of p38 inhibition (this co-culture was performed in vivo in cancer microscopically). Imitating the environment). As a result, all p38 inhibitors suppressed the proliferation of mouse CML stem cells.
さらに、イマチニブとp38阻害薬の併用効果を調べたところ、いずれのp38阻害薬も、イマチニブ単独の場合と比較して、マウスCML幹細胞のインビトロでの増殖をさらに抑制した。特にLY2228820において併用効果は顕著であった。 Furthermore, when the combined effect of imatinib and a p38 inhibitor was examined, all of the p38 inhibitors further suppressed the proliferation of mouse CML stem cells in vitro as compared to imatinib alone. In particular, the combined effect was remarkable in LY2228820.
CML患者から採取したヒトCML幹細胞についても、同様の方法で、p38阻害薬の単独投与及びダサチニブとの併用投与の効果を調べたところ、同様に、p38の選択的阻害は、インビトロでのヒトCML幹細胞の増殖を顕著に抑制した。 For human CML stem cells collected from CML patients, the effect of p38 inhibitor alone and in combination with dasatinib was examined in the same manner. Similarly, selective inhibition of p38 was also observed in human CML in vitro. Stem cell proliferation was significantly suppressed.
さらに、マウスCML幹細胞を移植したマウスを用いた実験から、p38阻害薬は単独で、インビボでCML幹細胞に対して優れた抑制効果を有することが示された。 Furthermore, experiments using mice transplanted with mouse CML stem cells showed that p38 inhibitors alone had an excellent suppressive effect on CML stem cells in vivo.
さらに重要なことに、ドキシサイクリン誘導型のCMLモデルマウスを用いた実験から、p38阻害薬とダサチニブとを併用すると、ダサチニブ単独投与に比べてマウスの生存率を顕著に改善することができた。
本発明者らは、以上の知見より、p38 MAPKシグナル伝達経路を阻害することにより、効率よくCML幹細胞を排除し、TKI抵抗性のCML幹細胞を抑制し得ること、さらにTKIと併用することにより、極めて優れたCML治療効果を奏することを見出して、本発明を完成するに至った。
More importantly, from experiments using doxycycline-induced CML model mice, the combination of p38 inhibitors and dasatinib significantly improved the survival rate of mice compared to dasatinib alone.
From the above findings, the present inventors can efficiently eliminate CML stem cells by inhibiting the p38 MAPK signal transduction pathway, and can suppress TKI-resistant CML stem cells, and in combination with TKI, The inventors have found that the CML therapeutic effect is extremely excellent, and have completed the present invention.
すなわち本発明は、以下の通りである。
〔1〕p38 MAPKシグナルの選択的阻害薬を含有してなる、慢性骨髄性白血病治療剤。
〔2〕阻害薬がp38α及びp38βを阻害するものである、上記〔1〕記載の剤。
〔3〕阻害薬がLY2228820、VX-702、BIRB 796及びそれらの塩からなる群より選択される、上記〔1〕又は〔2〕記載の剤。
〔4〕阻害薬がLY2228820又はその塩である、上記〔3〕記載の剤。
〔5〕慢性骨髄性白血病幹細胞の除去剤である、上記〔1〕〜〔4〕のいずれかに記載の剤。
〔6〕チロシンキナーゼ阻害薬に対して抵抗性の慢性骨髄性白血病幹細胞の抑制剤である、上記〔1〕〜〔4〕のいずれかに記載の剤。
〔7〕チロシンキナーゼ阻害薬又はマルチキナーゼ阻害薬と組み合わせてなる、上記〔1〕〜〔6〕のいずれかに記載の剤。
〔8〕チロシンキナーゼ阻害薬がイマチニブ、ダサチニブ、ボスチニブ、ラドチニブもしくはニロチニブであり、マルチキナーゼ阻害薬がKW2449もしくはポナチニブである、上記〔7〕記載の剤。
That is, the present invention is as follows.
[1] A therapeutic agent for chronic myelogenous leukemia, comprising a selective inhibitor of p38 MAPK signal.
[2] The agent described in [1] above, wherein the inhibitor inhibits p38α and p38β.
[3] The agent described in [1] or [2] above, wherein the inhibitor is selected from the group consisting of LY2228820, VX-702, BIRB 796 and salts thereof.
[4] The agent described in [3] above, wherein the inhibitor is LY2228820 or a salt thereof.
[5] The agent according to any one of [1] to [4] above, which is a remover of chronic myeloid leukemia stem cells.
[6] The agent according to any one of [1] to [4] above, which is an inhibitor of chronic myeloid leukemia stem cells resistant to tyrosine kinase inhibitors.
[7] The agent according to any one of [1] to [6] above, which is combined with a tyrosine kinase inhibitor or a multikinase inhibitor.
[8] The agent according to [7] above, wherein the tyrosine kinase inhibitor is imatinib, dasatinib, bosutinib, radotinib or nilotinib, and the multikinase inhibitor is KW2449 or ponatinib.
本発明によれば、p38阻害薬の投与により、TKI治療によれば根絶を免れる可能性のあるCML幹細胞、特に、従来のいずれのTKIに対しても抵抗性を示すCML幹細胞を、効率よく排除することができる。また、p38阻害薬とTKIあるいはマルチキナーゼ阻害薬との併用により、CMLの治療奏功性をより高めることができる。さらに、p38阻害薬との併用により、TKIあるいはマルチキナーゼ阻害薬の投与量の低減及び/又は投与期間の短縮を図ることができ、副作用を軽減させることができる。また、現在有効な治療がないBlast crisisやPh+ALL等のより悪性度の高い病態への進行を予防することができる。 According to the present invention, administration of a p38 inhibitor effectively eliminates CML stem cells that may be eradicated by TKI treatment, particularly CML stem cells that are resistant to any conventional TKI. can do. In addition, the combined use of a p38 inhibitor and a TKI or multikinase inhibitor can further improve the therapeutic efficacy of CML. Furthermore, by using in combination with a p38 inhibitor, the dose of TKI or multikinase inhibitor can be reduced and / or the administration period can be shortened, and side effects can be reduced. It can also prevent progression to more malignant conditions such as Blast crisis and Ph + ALL, for which no effective treatment is currently available.
本発明は、p38 MAPKシグナルの選択的阻害薬(本明細書においては、単に「p38阻害薬」ともいう)を含有してなる、慢性骨髄性白血病(CML)治療剤を提供する。
ここで「CML治療剤」とは、慢性期のCMLの治療のみならず、急性転化期や移行期のCMLの治療、急性転化の予防、CMLとPh+ALLの再発予防、再発CMLとPh+ALLの治療をも目的とする意味で用いられる。
また、ここで「p38 MAPKシグナル」とは、DNA損傷、酸化ストレス、紫外線、炎症性サイトカイン等の刺激により活性化されるMAPKKK(MEKK1-4、MLK2/3、ASK1、TAO1/2、TAK1)がMAPKK(MKK3/6、MKK4)を活性化し、活性化されたMAPKKがp38を活性化し、さらに活性化されたp38が種々の転写因子(Ets1、NFAT、Sap1、Stat1、Max、Myc、ELK1、p53、CHOP、MEF2、ATF2等)及びMAPKAPK(MK2/3、MSK1、MNK1/2)を活性化する、という一連のシグナル伝達カスケードを意味する。
The present invention provides a therapeutic agent for chronic myelogenous leukemia (CML) comprising a selective inhibitor of p38 MAPK signal (herein, also simply referred to as “p38 inhibitor”).
Here, “CML therapeutic agent” refers not only to the treatment of CML in the chronic phase, but also to the treatment of CML in the acute phase or transition phase, prevention of acute transformation, prevention of recurrence of CML and Ph + ALL, relapse CML and Ph + It is also used for the purpose of treating ALL.
In addition, “p38 MAPK signal” here refers to MAPKKK (MEKK1-4, MLK2 / 3, ASK1, TAO1 / 2, TAK1) activated by stimulation of DNA damage, oxidative stress, ultraviolet light, inflammatory cytokines, etc. Activates MAPKK (MKK3 / 6, MKK4), activated MAPKK activates p38, and activated p38 is a variety of transcription factors (Ets1, NFAT, Sap1, Stat1, Max, Myc, ELK1, p53 , CHOP, MEF2, ATF2, etc.) and MAPKAPK (MK2 / 3, MSK1, MNK1 / 2) are activated.
したがって、「p38 MAPKシグナルの選択的阻害薬(p38阻害薬)」とは、上記シグナル伝達経路のいずれかの段階を阻害するか、あるいは該シグナル伝達経路に動員される分子の発現自体を阻害することで、結果的に該シグナル伝達経路を選択的に阻害する薬剤であって、なおかつMAPKKKのさらに上流(例えば、TGF-β受容体、IL-1受容体、受容体チロシンキナーゼ(RTK)等)及びp38 MAPKシグナル以外のそれらの下流シグナル(例えば、TGF-βシグナルであれば、Smad経路、Ras経路、PI3K-Akt経路、ROCK経路等)を実質的に阻害しない薬剤を意味する。ここで「実質的に阻害しない」とは、全く阻害しない場合だけでなく、CMLの治療上有効な量において投与対象に対して悪影響を及ぼさえない程度にしか阻害しないことを意味し、例えば、p38 MAPKシグナルの標的分子に対するIC50値が他の生体分子に対するIC50値の1/10以下であり、好ましくは1/20以下、より好ましくは1/50以下、特に好ましくは1/100以下である。 Therefore, “a selective inhibitor of p38 MAPK signal (p38 inhibitor)” inhibits any step of the above signal transduction pathway, or inhibits the expression itself of a molecule mobilized in the signal transduction pathway. As a result, it is a drug that selectively inhibits the signal transduction pathway, and further upstream of MAPKKK (for example, TGF-β receptor, IL-1 receptor, receptor tyrosine kinase (RTK), etc.) And a p38 MAPK signal other than those downstream signals (for example, Tmad-β signal, Smad pathway, Ras pathway, PI3K-Akt pathway, ROCK pathway, etc.) Here, “substantially does not inhibit” means not only inhibiting at all, but also inhibiting to the extent that it does not even adversely affect the administration subject in a therapeutically effective amount of CML, for example, The IC 50 value for the target molecule of p38 MAPK signal is 1/10 or less of the IC 50 value for other biomolecules, preferably 1/20 or less, more preferably 1/50 or less, particularly preferably 1/100 or less. is there.
p38 MAPKシグナルの選択的阻害薬(p38阻害薬)としては、例えば、上記シグナル伝達経路のいずれかの段階を阻害する薬剤として、p38タンパク質に直接作用してその活性化(リン酸化)を阻害する物質、p38の上流のMAPKK(MKK3/6又はMKK4、好ましくはMKK3/6)に作用してp38の活性化(リン酸化)を阻害する物質、あるいはp38の基質(転写因子、MAPKAPK)に該基質の活性化(リン酸化)を阻害する物質等が挙げられるが、これらに限定されない。尚、p38にはα、β、γ及びδの4種のアイソフォームが存在するが、本発明のp38阻害薬は、それらの少なくとも1つのアイソフォームを阻害するものであればよく、例えば、少なくともp38αを阻害する薬剤が挙げられる。好ましくは、少なくともp38α及びp38βを阻害する薬剤である。好ましい一実施態様においては、本発明のp38阻害薬は、p38α及びp38βを選択的に阻害する薬剤である。 As a selective inhibitor of p38 MAPK signal (p38 inhibitor), for example, as a drug that inhibits any step of the above signal transduction pathway, it directly acts on p38 protein to inhibit its activation (phosphorylation) Substance, substance that acts on MAPKK upstream of p38 (MKK3 / 6 or MKK4, preferably MKK3 / 6) to inhibit p38 activation (phosphorylation), or substrate of p38 (transcription factor, MAPKAPK) Examples include, but are not limited to, substances that inhibit activation (phosphorylation). There are four isoforms of α, β, γ and δ in p38, but the p38 inhibitor of the present invention may be any one that inhibits at least one of these isoforms, for example, at least Examples include drugs that inhibit p38α. Preferably, it is an agent that inhibits at least p38α and p38β. In a preferred embodiment, the p38 inhibitor of the present invention is an agent that selectively inhibits p38α and p38β.
本発明のp38阻害薬としては、例えば、米国特許第7,582,652号明細書にATP競合阻害薬として作用するp38阻害薬として開示される、下記式(I): As the p38 inhibitor of the present invention, for example, the following formula (I) disclosed as a p38 inhibitor acting as an ATP competitive inhibitor in US Pat. No. 7,582,652:
(式中、Wは、下記式(i)〜(vii)のいずれかで表され; (Wherein, W is represented by any of the following formulas (i) to (vii);
Xは、窒素原子又はC−R1であり;
Rは、C1〜C7アルキル、C3〜C7シクロアルキル、(C1〜C7アルキレン)−(C3〜C7シクロアルキル)、−SO2−(C1〜C7アルキル)、又は−SO2−NR5R6であり;
R1は、水素原子、アミノ、メチル又は−N=CHN(CH3)2であり;
R2は、独立して選ばれる1又は2個のハロゲン原子で置換されていてもよいフェニルであり;
R3は、水素原子、C1〜C7アルキル、C3〜C7シクロアルキル、又はハロゲン原子及びトリフルオロメチルから独立して選ばれる1もしくは2個の置換基で置換されていてもよいフェニルであり;
R4は、水素原子又はC1〜C7アルキルであり;
R5及びR6は、それぞれ独立してC1〜C7アルキルである。)
で表される化合物又はその塩、
(ここで「C1〜C7アルキル」はメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチルを含み、「C1〜C7アルキレン」はメチレン、エチレン、プロピレン、イソプロピレン、ブチレン、イソブチレン、sec−ブチレン、tert−ブチレン、ペンチレン、ヘキシレン、ヘプチレンを含み、「C3〜C7シクロアルキル」はシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチルを含み、「(C1〜C7アルキレン)−(C3〜C7シクロアルキル)」はC1〜C7アルキレンリンカーを介して結合するC3〜C7シクロアルキルを意味し、「ハロゲン原子」はフッ素原子、塩素原子、臭素原子及びヨウ素原子を含む。)
X is a nitrogen atom or C—R 1 ;
R is, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, (C 1 -C 7 alkylene) - (C 3 ~C 7 cycloalkyl), - SO 2 - (C 1 ~C 7 alkyl), Or —SO 2 —NR 5 R 6 ;
R 1 is a hydrogen atom, amino, methyl, or —N═CHN (CH 3 ) 2 ;
R 2 is phenyl optionally substituted by 1 or 2 independently selected halogen atoms;
R 3 is a hydrogen atom, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, or phenyl optionally substituted with 1 or 2 substituents independently selected from a halogen atom and trifluoromethyl. Is;
R 4 is a hydrogen atom or C 1 -C 7 alkyl;
R 5 and R 6 are each independently C 1 -C 7 alkyl. )
Or a salt thereof,
(Wherein “C 1 -C 7 alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and “C 1 -C 7 alkylene” means methylene. , ethylene, propylene, isopropylene, butylene, isobutylene, sec- butylene, tert- butylene, pentylene, hexylene, includes a heptylene, "C 3 -C 7 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl Including, “(C 1 -C 7 alkylene)-(C 3 -C 7 cycloalkyl)” means a C 3 -C 7 cycloalkyl attached via a C 1 -C 7 alkylene linker, Is fluorine atom, chlorine atom, bromine atom and iodine atom Including the.)
好ましくは、下記式(I’): Preferably, the following formula (I ′):
(式中、R’は、2,2−ジメチルプロピル又は1,2,2−トリメチルプロピルであり;
R2’は、フェニル、4−フルオロフェニル又は2,4−ジフルオロフェニルであり;
R3’は、tert−ブチル、2−クロロ−6−フルオロフェニル、2−フルオロ−6−トリフルオロメチルフェニル、2,6−ジクロロフェニル又は2,6−ジフルオロフェニルである。)
で表される化合物又はその塩、
Wherein R ′ is 2,2-dimethylpropyl or 1,2,2-trimethylpropyl;
R 2 ′ is phenyl, 4-fluorophenyl or 2,4-difluorophenyl;
R 3 ′ is tert-butyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-trifluoromethylphenyl, 2,6-dichlorophenyl or 2,6-difluorophenyl. )
Or a salt thereof,
より好ましくは、上記式(1’)中:
(a) R’は2,2−ジメチルプロピル、R2’は4−フルオロフェニル及びR3’は2−フルオロ−6−トリフルオロメチルフェニル;
(b) R’は2,2−ジメチルプロピル、R2’は4−フルオロフェニル及びR3’は2,6−ジクロロフェニル;
(c) R’は2,2−ジメチルプロピル、R2’は4−フルオロフェニル及びR3’はtert−ブチル;
(d) R’は2,2−ジメチルプロピル、R2’はフェニル及びR3’は2−クロロ−6−フルオロフェニル;
(e) R’は2,2−ジメチルプロピル、R2’は2,4−ジフルオロフェニル;
(f) R’は1,2,2−トリメチルプロピル、R2’は4−フルオロフェニル及びR3’はtert−ブチル;又は
(g) R’は1,2,2−トリメチルプロピル、R2’は4−フルオロフェニル及びR3’は2,6−ジフルオロフェニル
である化合物又はその塩、
More preferably, in the above formula (1 ′):
(a) R ′ is 2,2-dimethylpropyl, R 2 ′ is 4-fluorophenyl and R 3 ′ is 2-fluoro-6-trifluoromethylphenyl;
(b) R ′ is 2,2-dimethylpropyl, R 2 ′ is 4-fluorophenyl and R 3 ′ is 2,6-dichlorophenyl;
(c) R ′ is 2,2-dimethylpropyl, R 2 ′ is 4-fluorophenyl and R 3 ′ is tert-butyl;
(d) R ′ is 2,2-dimethylpropyl, R 2 ′ is phenyl and R 3 ′ is 2-chloro-6-fluorophenyl;
(e) R ′ is 2,2-dimethylpropyl, R 2 ′ is 2,4-difluorophenyl;
(f) R ′ is 1,2,2-trimethylpropyl, R 2 ′ is 4-fluorophenyl and R 3 ′ is tert-butyl; or
(g) a compound or a salt thereof, wherein R ′ is 1,2,2-trimethylpropyl, R 2 ′ is 4-fluorophenyl and R 3 ′ is 2,6-difluorophenyl;
特に好ましくは、上記式(1’)中、R’は2,2−ジメチルプロピル、R2’は4−フルオロフェニル及びR3’はtert−ブチルである化合物〔5−(2−tert−ブチル−5−(4−フルオロフェニル)−1H−イミダゾール−4−イル)−3−ネオペンチル−3H−イミダゾ[4,5−b]ピリジン−2−アミン(ラリメチニブ(LY2228820);図1);本明細書においては、「LY2228820」と称する場合がある。〕又はその塩が挙げられる。LY2228820はp38α及びp38βに選択的なp38阻害剤である。
上記式(I)又は(I’)で表される化合物の塩としては、医薬上許容される塩であれば特に制限はないが、例えば、トリフルオロ酢酸、酢酸、乳酸、コハク酸、マレイン酸、酒石酸、クエン酸、グルコン酸、アスコルビン酸、安息香酸、メタンスルホン酸、p−トルエンスルホン酸、ケイ皮酸、フマル酸、ホスホン酸、塩酸、硝酸、臭化水素酸、ヨウ化水素酸、スルファミン酸、硫酸等の酸との酸付加塩、好ましくはメタンスルホン酸塩、コハク酸塩、フマル酸塩、二マレイン酸塩、二塩酸塩、二メタンスルホン酸塩等、より好ましくは二メタンスルホン酸塩が挙げられる。
Particularly preferably, in the above formula (1 ′), R ′ is 2,2-dimethylpropyl, R 2 ′ is 4-fluorophenyl and R 3 ′ is tert-butyl [5- (2-tert-butyl -5- (4-Fluorophenyl) -1H-imidazol-4-yl) -3-neopentyl-3H-imidazo [4,5-b] pyridin-2-amine (ralimetinib (LY2228820); FIG. 1); In the book, it may be referred to as “LY2228820”. Or a salt thereof. LY2228820 is a p38 inhibitor selective for p38α and p38β.
The salt of the compound represented by the above formula (I) or (I ′) is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid , Tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamine Acid addition salts with acids such as sulfuric acid, preferably methanesulfonate, succinate, fumarate, dimaleate, dihydrochloride, dimethanesulfonate, etc., more preferably dimethanesulfonic acid Salt.
また、別の本発明のp38阻害薬として、例えば、Nikasら(Curr Opin Drug Discov Devel. 8, 421-430(2005))に開示されるAMG-548、BIRB-796(図1)、SClO-469、SCIO-323、VX-702(図1)、WO 2011/087795に開示されるペキシメチニブ(ARRY-614)及びその誘導体、WO 99/42592に開示される、ATP競合阻害薬として作用するSB203580、SB202190及びそれらの誘導体、Underwoodら(J Pharmacol Exp Ther. 293, 281-288 (2000))に開示される、SB239063及びその誘導体、Jacksonら(J Pharmacol Exp Ther. 284, 687-692 (1998))に開示されるSB220025及びその誘導体、Gallagherら(Bioorg. Med. Chem. 5, 49 (1997) )に開示されるPD169316、Mclayら(Bioorg Med Chem.9, 537-554 (2001))に開示されるRPR200765A、Yamamotoら(Eur. J. Pharmacol. 314, 137-142 (1996))に開示されるFR167653、Astonら(J. Med. Chem. 52, 6257 (2009))に開示されるロスマピモド(GW856553X)、Xingら(Biochem. 48, 6402-6411 (2009))、Haddad(Curr. Opin. Investig. Drugs 2, 1070-1076 (2001))に開示されるVX-745、Miwatashiら(J. Med. Chem. 48, 5966-5979 (2005))、Koeberleら(Nat. Chem. Biol. 8, 141-143 (2012))に開示されるスケピノン-L、並びにそれらの塩が挙げられる。 Further, as another p38 inhibitor of the present invention, for example, AMG-548, BIRB-796 (FIG. 1), SClO— disclosed in Nikas et al. (Curr Opin Drug Discov Devel. 8, 421-430 (2005)). 469, SCIO-323, VX-702 (FIG. 1), peximetinib (ARRY-614) and its derivatives disclosed in WO 2011/087795, SB203580 acting as an ATP competitive inhibitor disclosed in WO 99/42592, SB202190 and derivatives thereof, disclosed in Underwood et al. (J Pharmacol Exp Ther. 293, 281-288 (2000)), SB239063 and derivatives thereof, Jackson et al. (J Pharmacol Exp Ther. 284, 687-692 (1998)) SB220025 and derivatives thereof disclosed in PD169316, Mclay et al. (Bioorg Med Chem. 9, 537-554 (2001)) disclosed in Gallagher et al. (Bioorg. Med. Chem. 5, 49 (1997)). RPR200765A, FR167653 disclosed in Yamamoto et al. (Eur. J. Pharmacol. 314, 137-142 (1996)), Rosmapimod (GW856553X disclosed in Aston et al. (J. Med. Chem. 52, 6257 (2009)) ), Xing et al. (Bioche m. 48, 6402-6411 (2009)), Haddad (Curr. Opin. Investig. Drugs 2, 1070-1076 (2001)), VX-745, Miwatashi et al. (J. Med. Chem. 48, 5966) -5979 (2005)), Koeberle et al. (Nat. Chem. Biol. 8, 141-143 (2012)), and skepinone-L, and salts thereof.
上記の化合物の塩としては、医薬上許容される塩であれば特に制限はないが、例えば、トリフルオロ酢酸、酢酸、乳酸、コハク酸、マレイン酸、酒石酸、クエン酸、グルコン酸、アスコルビン酸、安息香酸、メタンスルホン酸、p−トルエンスルホン酸、ケイ皮酸、フマル酸、ホスホン酸、塩酸、硝酸、臭化水素酸、ヨウ化水素酸、スルファミン酸、硫酸等の酸との酸付加塩;例えば、ナトリウム、カリウム、マグネシウム、カルシウム等の金属塩;例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、N−メチルピロリジン、N−メチルピペリジン、N−メチルモルホリン等の有機塩基との塩等が挙げられる。 The salt of the above compound is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, Acid addition salts with acids such as benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid; For example, metal salts such as sodium, potassium, magnesium and calcium; for example, salts with organic bases such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine and N-methylmorpholine.
上記した本発明の低分子p38阻害薬が、光学異性体、立体異性体、位置異性体、回転異性体等の異性体を有する場合には、いずれか一方の異性体も、異性体の混合物も、阻害活性を有する限り本発明のp38阻害薬に包含される。例えば、本発明のp38阻害薬に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も本発明のp38阻害薬に包含される。これらの異性体は、自体公知の合成手法、分離手法(濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶等)によりそれぞれを単品として得ることができる。
上記した本発明の低分子p38阻害薬は、結晶であっても無晶形であってもよい。該p38阻害薬が結晶である場合、結晶形が単一であっても結晶形混合物であっても、本発明のp38阻害薬に包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。
本発明の低分子p38阻害薬は、溶媒和物(例えば、水和物等)であっても、無溶媒和物であってもよく、いずれも本発明のp38阻害薬に包含される。
本発明の低分子p38阻害薬は、同位元素(例、3H,14C,35S,125I等)等で標識されていてもよい。
また、本発明のp38低分子阻害薬が酸に不安定な場合、経口投与する場合には胃酸による分解を防ぐために、自体公知の方法により酸に安定なプロドラッグの形態で提供され得る。
When the above-described low-molecular-weight p38 inhibitor of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one isomer or a mixture of isomers As long as it has inhibitory activity, it is included in the p38 inhibitor of the present invention. For example, when an optical isomer exists in the p38 inhibitor of the present invention, the optical isomer resolved from the racemate is also encompassed in the p38 inhibitor of the present invention. Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
The above-described low molecular weight p38 inhibitor of the present invention may be crystalline or amorphous. When the p38 inhibitor is a crystal, a single crystal form or a mixture of crystal forms is included in the p38 inhibitor of the present invention. The crystal can be produced by crystallization by applying a crystallization method known per se.
The low molecular weight p38 inhibitor of the present invention may be a solvate (for example, hydrate etc.) or a solvate, and both are included in the p38 inhibitor of the present invention.
The low molecular weight p38 inhibitor of the present invention may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
In addition, when the p38 small molecule inhibitor of the present invention is unstable to acid, it can be provided in the form of an acid-stable prodrug by a method known per se to prevent degradation by gastric acid when administered orally.
上記した本発明の低分子p38阻害薬はいずれも公知化合物であり、それぞれ自体公知の方法により製造することができる。また、これらのp38阻害薬の多くは市販されている。 The above-described low molecular weight p38 inhibitors of the present invention are all known compounds and can be produced by methods known per se. In addition, many of these p38 inhibitors are commercially available.
その他、p38のリン酸化を阻害する物質としては、p38を模倣するMKK3/6、MKK4の基質ペプチド、該MAPKKのドミナントネガティブ体、p38のリン酸化を立体的に妨害する抗体やアプタマー等が挙げられる。p38による下流因子(転写因子、MAPAPK)のリン酸化を阻害する物質としては、該下流因子を模倣するp38の基質ペプチド、p38のドミナントネガティブ体等が挙げられる。p38やその下流因子を模倣する基質ペプチドは、各タンパク質のリン酸化部位を含む部分アミノ酸配列からなるペプチドを、自体公知の方法により化学合成することにより製造することができる。p38に対する抗体やアプタマーも自体公知の方法により取得することができる。
p38のドミナントネガティブ体としては、基質結合能を有するものの、基質をリン酸化させることなく、野生型p38タンパク質と競合的に作用して、その機能を阻害する限り、いかなる物質であってもよい。例えば、ヒトおよびマウスにおけるp38のDNA結合領域に位置する180位のスレオニンをアラニンに点変異させたp38T180A、ヒトおよびマウスにおけるp38の182位のチロシンをフェニルアラニンに点変異させたp38Y182Fなどが挙げられる(Raingeaud J., J Biol Chem. 270, 7420-7426. (1995))。
p38のドミナントネガティブ体は、例えば、以下の手法により得ることができる。ヒトp38においては、p38αの場合はNCBIデータベースのNM_001315、p38βの場合はNM_002751として登録されている配列に基づいて適当なオリゴヌクレオチドをプローブもしくはプライマーとして合成し、ヒトの細胞・組織由来のmRNA、cDNAもしくはcDNAライブラリーから、ハイブリダイゼーション法や(RT-)PCR法を用いてマウスまたはヒトp38 cDNAをクローニングし、適当なプラスミドにサブクローニングする。変異を導入しようとする部位のコドンを所望の他のアミノ酸をコードするコドンに置換した形で、当該部位を含むプライマーを合成し、これを用いてp38cDNAを挿入したプラスミドを鋳型とするインバースPCRを行うことにより、目的のドミナントネガティブ体をコードする核酸を取得する。p38DDのような欠失変異体の場合には、欠失させる部位の外側にプライマーを設計して、同様にインバースPCRを行えばよい。
MAPKKのドミナントネガティブ体についても同様である。
In addition, examples of substances that inhibit p38 phosphorylation include MKK3 / 6 that mimics p38, MKK4 substrate peptide, dominant negative form of MAPKK, antibodies and aptamers that sterically hinder p38 phosphorylation, etc. . Examples of the substance that inhibits phosphorylation of a downstream factor (transcription factor, MAPAPK) by p38 include a substrate peptide of p38 that mimics the downstream factor, a dominant negative form of p38, and the like. A substrate peptide that mimics p38 or its downstream factor can be produced by chemically synthesizing a peptide consisting of a partial amino acid sequence including the phosphorylation site of each protein by a method known per se. Antibodies and aptamers against p38 can also be obtained by methods known per se.
The dominant negative form of p38 may be any substance as long as it has a substrate binding ability but acts competitively with the wild-type p38 protein and inhibits its function without phosphorylating the substrate. Examples include p38T180A in which threonine at position 180 located in the DNA binding region of p38 in humans and mice is point-mutated to alanine, p38Y182F in which tyrosine at position 182 of p38 in humans and mice is point-mutated to phenylalanine, and the like ( Raingeaud J., J Biol Chem. 270, 7420-7426. (1995)).
A dominant negative form of p38 can be obtained, for example, by the following method. In human p38, for p38α, synthesize an appropriate oligonucleotide as a probe or primer based on the sequence registered as NM_001315 in the NCBI database for p38α, and NM_002751 for p38β. Alternatively, mouse or human p38 cDNA is cloned from a cDNA library using a hybridization method or (RT-) PCR method and subcloned into an appropriate plasmid. Inverse PCR using the plasmid containing the inserted p38 cDNA as a template by synthesizing a primer containing the site in which the codon at the site where the mutation is to be introduced is replaced with a codon encoding another desired amino acid. By performing, a nucleic acid encoding the target dominant negative body is obtained. In the case of a deletion mutant such as p38DD, a primer may be designed outside the site to be deleted, and inverse PCR may be performed in the same manner.
The same applies to the dominant negative form of MAPKK.
p38の発現を阻害するp38 MAPKシグナルの選択的阻害薬としては、p38に対するアンチセンス核酸、siRNA(shRNA)、リボザイムなどが挙げられる。好ましくはsiRNA(shRNA)である。p38に対するsiRNAは、配列番号1〜4に示されるマウスまたはヒトの各p38 cDNA配列情報に基づいて、例えば、Elbashirら(Genes Dev., 15, 188-200 (2001))の提唱する規則に従って設計することができる。選択された標的配列の候補群について、標的以外のmRNAにおいて16-17塩基の連続した配列に相同性がないかどうかを、BLAST(http://www.ncbi.nlm.nih.gov/BLAST/)等のホモロジー検索ソフトを用いて調べ、選択した標的配列の特異性を確認する。特異性の確認された標的配列について、AA(もしくはNA)以降の19-21塩基にTTもしくはUUの3’末端オーバーハングを有するセンス鎖と、該19-21塩基に相補的な配列及びTTもしくはUUの3’末端オーバーハングを有するアンチセンス鎖とからなる2本鎖RNAをsiRNAとして設計する。また、shRNAは、ループ構造を形成しうる任意のリンカー配列(例えば、8-25塩基程度)を適宜選択し、上記センス鎖とアンチセンス鎖とを該リンカー配列を介して連結することにより設計することができる。 Examples of selective inhibitors of the p38 MAPK signal that inhibit the expression of p38 include antisense nucleic acids, siRNA (shRNA), ribozymes, and the like against p38. Preferably it is siRNA (shRNA). The siRNA for p38 is designed according to the rules proposed by Elbashir et al. (Genes Dev., 15, 188-200 (2001)) based on the mouse or human p38 cDNA sequence information shown in SEQ ID NOs: 1-4. can do. For the selected target sequence candidate group, whether or not there is homology in the 16-17 base sequence in the non-target mRNA is determined by BLAST (http://www.ncbi.nlm.nih.gov/BLAST/ ) And the like, and the specificity of the selected target sequence is confirmed. About the target sequence whose specificity has been confirmed, a sense strand having a 3 'end overhang of TT or UU at 19-21 bases after AA (or NA), a sequence complementary to the 19-21 bases and TT or A double-stranded RNA consisting of an antisense strand having a 3 'end overhang of UU is designed as an siRNA. The shRNA is designed by appropriately selecting an arbitrary linker sequence (for example, about 8-25 bases) that can form a loop structure, and linking the sense strand and the antisense strand via the linker sequence. be able to.
siRNA及び/又はshRNAの配列は、種々のwebサイト上に無料で提供される検索ソフトを用いて検索が可能である。このようなサイトとしては、例えば、Ambionが提供するsiRNA Target Finder(http://www.ambion.com/jp/techlib/misc/siRNA_finder.html)及びpSilencerTM Expression Vector用 インサート デザインツール(http://www.ambion.com/jp/techlib/misc/psilencer_converter.html)、RNAi Codexが提供するGeneSeer(http://codex.cshl.edu/scripts/newsearchhairpin.cgi)がこれらに限定されず、QIAGEN、タカラバイオ、SiSearch、Dharmacon、Whitehead Institute、Invitrogen、Promega等のwebサイト上でも同様に検索が可能である。 The sequence of siRNA and / or shRNA can be searched using search software provided free of charge on various websites. Examples of such sites include siRNA Target Finder (http://www.ambion.com/jp/techlib/misc/siRNA_finder.html) and pSilencer ™ Expression Vector insert design tool (http: / /www.ambion.com/techlib/misc/psilencer_converter.html), GeneSeer provided by RNAi Codex (http://codex.cshl.edu/scripts/newsearchhairpin.cgi) is not limited to these, QIAGEN, Searches are also possible on websites such as Takara Bio, SiSearch, Dharmacon, Whitehead Institute, Invitrogen, and Promega.
p38に対するsiRNAは、上記のようにして設計されたセンス鎖及びアンチセンス鎖オリゴヌクレオチドをDNA/RNA自動合成機でそれぞれ合成し、例えば、適当なアニーリング緩衝液中、約90〜約95℃で約1分程度変性させた後、約30〜約70℃で約1〜約8時間アニーリングさせることにより調製することができる。また、p38に対するshRNAは、上記のようにして設計されたshRNA配列を有するオリゴヌクレオチドをDNA/RNA自動合成機で合成し、上記と同様にしてセルフアニーリングさせることによって調製することができる。 The siRNA for p38 was synthesized by using a DNA / RNA automatic synthesizer with the sense strand and antisense strand oligonucleotides designed as described above, for example, at about 90 to about 95 ° C. in a suitable annealing buffer. It can be prepared by denaturing for about 1 minute and then annealing at about 30 to about 70 ° C. for about 1 to about 8 hours. ShRNA against p38 can be prepared by synthesizing an oligonucleotide having the shRNA sequence designed as described above with a DNA / RNA automatic synthesizer and self-annealing in the same manner as described above.
siRNA及びshRNAを構成するヌクレオチド分子は、天然型のRNAでもよいが、安定性(化学的および/または対酵素)や比活性(mRNAとの親和性)を向上させるために、種々の化学修飾を含むことができる。例えば、ヌクレアーゼなどの加水分解酵素による分解を防ぐために、アンチセンス核酸を構成する各ヌクレオチドのリン酸残基(ホスフェート)を、例えば、ホスホロチオエート(PS)、メチルホスホネート、ホスホロジチオネートなどの化学修飾リン酸残基に置換することができる。また、各ヌクレオチドの糖(リボース)の2'位の水酸基を、-OR(Rは、例えばCH3(2'-O-Me)、CH2CH2OCH3(2'-O-MOE)、CH2CH2NHC(NH)NH2、CH2CONHCH3、CH2CH2CN等を示す)に置換してもよい。さらに、塩基部分(ピリミジン、プリン)に化学修飾を施してもよく、例えば、ピリミジン塩基の5位へのメチル基やカチオン性官能基の導入、あるいは2位のカルボニル基のチオカルボニルへの置換などが挙げられる。 The nucleotide molecules that make up siRNA and shRNA may be natural RNA, but various chemical modifications may be applied to improve stability (chemical and / or enzyme) and specific activity (affinity with mRNA). Can be included. For example, in order to prevent degradation by a hydrolase such as nuclease, the phosphate residue (phosphate) of each nucleotide constituting the antisense nucleic acid is chemically modified, for example, phosphorothioate (PS), methylphosphonate, phosphorodithionate, etc. It can be substituted with a phosphate residue. In addition, the 2′-position hydroxyl group of the sugar (ribose) of each nucleotide is represented by —OR (R is, for example, CH 3 (2′-O-Me), CH 2 CH 2 OCH 3 (2′-O-MOE), CH 2 CH 2 NHC (NH) NH 2 , CH 2 CONHCH 3 , CH 2 CH 2 CN and the like may be substituted). Furthermore, the base moiety (pyrimidine, purine) may be chemically modified, for example, introduction of a methyl group or a cationic functional group at the 5-position of the pyrimidine base, or substitution of the carbonyl group at the 2-position with thiocarbonyl. Is mentioned.
RNAの糖部のコンフォーメーションはC2'-endo(S型)とC3'-endo(N型)の2つが支配的であり、一本鎖RNAではこの両者の平衡として存在するが、二本鎖を形成するとN型に固定される。したがって、標的RNAに対して強い結合能を付与するために、2'酸素と4’炭素を架橋することにより、糖部のコンフォーメーションをN型に固定したRNA誘導体であるBNA(LNA)(Imanishi, T. et al., Chem. Commun., 1653-9, 2002; Jepsen, J.S. et al., Oligonucleotides, 14, 130-46, 2004)やENA(Morita, K. et al., Nucleosides Nucleotides Nucleic Acids, 22, 1619-21, 2003)もまた、好ましく用いられ得る。 The conformation of the sugar part of RNA is dominated by C2'-endo (S type) and C3'-endo (N type). In single-stranded RNA, it exists as an equilibrium between the two, but double-stranded Is fixed to the N type. Therefore, in order to give strong binding ability to the target RNA, BNA (LNA) (Imanishi) is an RNA derivative in which the conformation of the sugar moiety is fixed to N-type by cross-linking 2 'oxygen and 4' carbon. , T. et al., Chem. Commun., 1653-9, 2002; Jepsen, JS et al., Oligonucleotides, 14, 130-46, 2004) and ENA (Morita, K. et al., Nucleosides Nucleotides Nucleicides Nucleic Acids , 22, 1619-21, 2003) can also be preferably used.
但し、天然型RNA中のすべてのリボヌクレオシド分子を修飾型で置換すると、RNAi活性が失われる場合があるので、RISC複合体が機能できる最小限の修飾ヌクレオシドの導入が必要である。 However, if all ribonucleoside molecules in the natural RNA are replaced with a modified form, RNAi activity may be lost, and therefore it is necessary to introduce a minimal modified nucleoside that allows the RISC complex to function.
p38に対するsiRNAは、例えば、Santa Cruz(例、Santa Cruz Cat# sc-29433, sc-29434, sc-44216 )、SigmaAldrich (例、SHGLY-NM_011951)等から購入することもできる。 The siRNA for p38 can also be purchased from, for example, Santa Cruz (eg, Santa Cruz Cat # sc-29433, sc-29434, sc-44216), SigmaAldrich (eg, SHGLY-NM_011951), and the like.
本発明のp38阻害薬は、CML幹細胞、特にTKIに抵抗性を示すCML幹細胞を、効率よく排除することができるので、CMLの治療、並びに、現在有効な治療がないBlast crisisやPh+ALL等のより悪性度の高い病態への進展抑制に有効である。 Since the p38 inhibitor of the present invention can efficiently eliminate CML stem cells, particularly CML stem cells that are resistant to TKI, treatment of CML and Blast crisis, Ph + ALL, etc. for which there is currently no effective treatment It is effective in suppressing the progression to higher-grade disease states.
近年、種々のがんにおいてp38が活性化されていること、p38阻害薬は黒色腫、非小細胞肺癌、卵巣癌、神経膠腫、骨髄腫、乳癌など複数の腫瘍モデルで腫瘍の増殖を抑制したことが報告され、LY2228820、LY3007113、ARRY-614の3剤について第1相又は第2相試験が米仏で実施されている。しかしながら、CMLに対しては、p38の活性化はCML細胞にアポトーシスを誘導し、逆にCML細胞株K562細胞においてp38を阻害するとアポトーシスが抑制されることや、ダサチニブのCML治療効果にはp38の活性化が必須であること等が報告されており、p38を阻害するとCMLをむしろ悪化させる可能性が示唆されていた。従って、本発明において、p38を阻害することによりin vivoでCML治療効果が認められたことは驚くべき発見である。 In recent years, p38 has been activated in various cancers, and p38 inhibitors suppress tumor growth in multiple tumor models including melanoma, non-small cell lung cancer, ovarian cancer, glioma, myeloma, and breast cancer A phase I or phase II trial is being conducted in the US and France for the three drugs LY2228820, LY3007113, and ARRY-614. However, for CML, activation of p38 induces apoptosis in CML cells, and conversely, inhibition of p38 in CML cell line K562 cells suppresses apoptosis, and the effect of p38 on the therapeutic effect of dasatinib on CML It has been reported that activation is essential, and it has been suggested that inhibition of p38 may worsen CML. Therefore, in the present invention, it is a surprising discovery that CML therapeutic effect was recognized in vivo by inhibiting p38.
本発明の低分子p38阻害薬、MAPKK(MKK3/6、MKK4)の基質ペプチド、該MAPKKのドミナントネガティブ体、p38のリン酸化を立体的に妨害する抗体、p38の基質ペプチド、p38のドミナントネガティブ体等を医薬品(即ち、CML治療剤)として用いるにあたり、そのまま、もしくは公知の薬理学的に許容される担体などと混合して医薬組成物として調製することができる。当該医薬組成物は、調製する形態(錠剤、丸剤、カプセル剤、散剤、顆粒剤、シロップ剤、乳剤、懸濁液などの経口投与剤;注射剤、点滴剤、外用剤、坐剤などの非経口投与剤)等に応じて、全身的にまたは局所的に、経口投与または非経口投与することができる。非経口投与する場合には、静脈内投与、皮内投与、皮下投与、直腸投与、経皮投与すること等が可能である。 Small molecule p38 inhibitor of the present invention, MAPKK (MKK3 / 6, MKK4) substrate peptide, dominant negative form of the MAPKK, antibody that sterically interferes with phosphorylation of p38, substrate peptide of p38, dominant negative form of p38 Can be prepared as a pharmaceutical composition as it is or by mixing it with a known pharmacologically acceptable carrier or the like. The pharmaceutical composition is prepared in an orally administered form such as tablets, pills, capsules, powders, granules, syrups, emulsions and suspensions; injections, drops, external preparations, suppositories, etc. Depending on the parenteral administration agent, etc., it can be systemically or locally administered orally or parenterally. In the case of parenteral administration, intravenous administration, intradermal administration, subcutaneous administration, rectal administration, transdermal administration, and the like are possible.
本発明のCML治療剤中の、上記p38阻害薬の含有量は、組成物全体の約0.01重量%〜100重量%である。 The content of the p38 inhibitor in the CML therapeutic agent of the present invention is about 0.01% to 100% by weight of the total composition.
前記の適当な投与剤型は薬理学的に許容される担体等に有効成分を配合することにより製造することができる。薬理学的に許容される担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が挙げられ、例えば、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、水溶性高分子、塩基性無機塩;液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等があげられる。また、必要に応じて、通常の防腐剤、抗酸化剤、着色剤、甘味剤、酸味剤、発泡剤、香料等の添加物を用いることもできる。 The above-mentioned appropriate dosage form can be produced by blending the active ingredient with a pharmacologically acceptable carrier or the like. Examples of the pharmacologically acceptable carrier include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials, such as excipients, lubricants, binders, disintegrants, water-soluble polymers in solid formulations, Basic inorganic salts; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like in liquid preparations. Further, if necessary, additives such as ordinary preservatives, antioxidants, colorants, sweeteners, sour agents, foaming agents, and fragrances can be used.
該「賦形剤」としては、例えば、乳糖、白糖、D−マンニトール、でんぷん、コーンスターチ、結晶セルロース、軽質無水ケイ酸、酸化チタン等が挙げられる。 Examples of the “excipient” include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.
該「滑沢剤」としては、例えば、ステアリン酸マグネシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸等が挙げられる。 Examples of the “lubricant” include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
該「結合剤」としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、結晶セルロース、デンプン、ポリビニルピロリドン、アラビアゴム末、ゼラチン、プルラン、低置換度ヒドロキシプロピルセルロース等が挙げられる。 Examples of the “binder” include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropylcellulose, and the like.
該「崩壊剤」としては、(1)クロスポビドン、(2)クロスカルメロースナトリウム(FMC−旭化成)、カルメロースカルシウム(五徳薬品)等スーパー崩壊剤と称される崩壊剤、(3)カルボキシメチルスターチナトリウム(例、松谷化学(株)製)、(4)低置換度ヒドロキシプロピルセルロース(例、信越化学(株)製)、(5)コーンスターチ等が挙げられる。該「クロスポピドン」としては、ポリビニルポリピロリドン(PVPP)、1−ビニル−2−ピロリジノンホモポリマーと称されているものも含め、1−エテニル−2−ピロリジノンホモポリマーという化学名を有し架橋されている重合物のいずれであってもよく、具体例としては、コリドンCL(BASF社製)、ポリプラスドンXL(ISP社製)、ポリプラスドンXL−10(ISP社製)、ポリプラスドンINF−10(ISP社製)等である。 Examples of the “disintegrant” include (1) crospovidone, (2) disintegrant called super disintegrant such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Pharmaceutical), (3) carboxymethyl Examples include starch sodium (eg, Matsutani Chemical Co., Ltd.), (4) low-substituted hydroxypropylcellulose (eg, Shin-Etsu Chemical Co., Ltd.), (5) corn starch and the like. The “crospovidone” is crosslinked with a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinyl polypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer. Specific examples include Kollidon CL (manufactured by BASF), Polyplaston XL (manufactured by ISP), Polyplaston XL-10 (manufactured by ISP), and Polyplastidone. INF-10 (manufactured by ISP) or the like.
該「水溶性高分子」としては、例えば、エタノール可溶性水溶性高分子〔例えば、ヒドロキシプロピルセルロース(以下、HPCと記載することがある)等のセルロース誘導体、ポリビニルピロリドン等〕、エタノール不溶性水溶性高分子〔例えば、ヒドロキシプロピルメチルセルロース(以下、HPMCと記載することがある)、メチルセルロース、カルボキシメチルセルロースナトリウム等のセルロース誘導体、ポリアクリル酸ナトリウム、ポリビニルアルコール、アルギン酸ナトリウム、グアーガム等〕等が挙げられる。 Examples of the “water-soluble polymer” include ethanol-soluble water-soluble polymers [for example, cellulose derivatives such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, etc.], ethanol-insoluble water-soluble polymers Molecules [for example, hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC), cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum, etc.] and the like.
該「塩基性無機塩」としては、例えば、ナトリウム、カリウム、マグネシウムおよび/またはカルシウムの塩基性無機塩が挙げられる。好ましくはマグネシウムおよび/またはカルシウムの塩基性無機塩である。さらに好ましくはマグネシウムの塩基性無機塩である。該ナトリウムの塩基性無機塩としては、例えば、炭酸ナトリウム、炭酸水素ナトリウム、リン酸水素二ナトリウム等が挙げられる。該カリウムの塩基性無機塩としては、例えば、炭酸カリウム、炭酸水素カリウム等が挙げられる。該マグネシウムの塩基性無機塩としては、例えば、重質炭酸マグネシウム、炭酸マグネシウム、酸化マグネシウム、水酸化マグネシウム、メタ珪酸アルミン酸マグネシウム、珪酸マグネシウム、アルミン酸マグネシウム、合成ヒドロタルサイト〔Mg6Al2(OH)16・CO3・4H2O〕および水酸化アルミナ・マグネシウム、好ましくは、重質炭酸マグネシウム、炭酸マグネシウム、酸化マグネシウム、水酸化マグネシウム等が挙げられる。該カルシウムの塩基性無機塩としては、例えば、沈降炭酸カルシウム、水酸化カルシウム等が挙げられる。 Examples of the “basic inorganic salt” include basic inorganic salts of sodium, potassium, magnesium and / or calcium. Preferred is a basic inorganic salt of magnesium and / or calcium. More preferred is a basic inorganic salt of magnesium. Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like. Examples of the basic inorganic salt of potassium include potassium carbonate and potassium hydrogen carbonate. Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 ( OH) 16 · CO 3 · 4H 2 O] and alumina / magnesium hydroxide, preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.
該「溶剤」としては、例えば、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油等が挙げられる。 Examples of the “solvent” include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
該「溶解補助剤」としては、例えば、ポリエチレングリコール、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。 Examples of the “dissolution aid” include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
該「懸濁化剤」としては、例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤;例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等が挙げられる。 Examples of the “suspending agent” include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
該「等張化剤」としては、例えば、ブドウ糖、 D−ソルビトール、塩化ナトリウム、グリセリン、D−マンニトール等が挙げられる。 Examples of the “isotonic agent” include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
該「緩衝剤」としては、例えば、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等が挙げられる。 Examples of the “buffering agent” include buffer solutions of phosphate, acetate, carbonate, citrate, and the like.
該「無痛化剤」としては、例えばベンジルアルコール等が挙げられる。 Examples of the “soothing agent” include benzyl alcohol and the like.
該「防腐剤」としては、例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。 Examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
該「抗酸化剤」としては、例えば、亜硫酸塩、アスコルビン酸、α−トコフェロール等が挙げられる。 Examples of the “antioxidant” include sulfite, ascorbic acid, α-tocopherol and the like.
該「着色剤」としては、例えば、食用黄色5号、食用赤色2号、食用青色2号等の食用色素;食用レーキ色素、ベンガラ等が挙げられる。 Examples of the “colorant” include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments, bengara and the like.
該「甘味剤」としては、例えば、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチン等が挙げられる。 Examples of the “sweetening agent” include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
該「酸味剤」としては、例えば、クエン酸(無水クエン酸)、酒石酸、リンゴ酸等が挙げられる。 Examples of the “sour agent” include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.
該「発泡剤」としては、例えば重曹等が挙げられる。 Examples of the “foaming agent” include sodium bicarbonate.
該「香料」としては、合成物および天然物のいずれでもよく、例えば、レモン、ライム、オレンジ、メントール、ストロベリー等が挙げられる。 The “fragrance” may be a synthetic product or a natural product, and examples thereof include lemon, lime, orange, menthol, and strawberry.
本発明の低分子p38阻害薬は、自体公知の方法に従い、例えば、賦形剤、崩壊剤、結合剤または滑沢剤等の担体を添加して圧縮成形し、次いで必要により、味のマスキング、腸溶性あるいは持続性の目的のため自体公知の方法でコーティングすることにより経口投与製剤とすることができる。腸溶性製剤とする場合、腸溶層と薬剤含有層との間に両層の分離を目的として、自体公知の方法により中間層を設けることもできる。 The low molecular weight p38 inhibitor of the present invention is compression-molded according to a method known per se, for example, by adding a carrier such as an excipient, a disintegrant, a binder or a lubricant, and then, if necessary, masking of taste, For enteric or long-lasting purposes, an oral preparation can be obtained by coating by a method known per se. In the case of an enteric preparation, an intermediate layer may be provided between the enteric layer and the drug-containing layer by a method known per se for the purpose of separating both layers.
本発明の低分子p38阻害薬を例えば口腔内崩壊錠とする場合、例えば、結晶セルロースおよび乳糖を含有する核を、本発明の低分子p38阻害薬および必要により塩基性無機塩で被覆し、さらに水溶性高分子含有被覆層で被覆して組成物を得、得られた組成物をポリエチレングリコール含有腸溶性被覆層で被覆し、次にクエン酸トリエチル含有腸溶性被覆層で被覆し、さらにポリエチレングリコール含有腸溶性被覆層で被覆し、最後にマンニトールで被覆して細粒を得、得られた細粒と添加剤とを混合し、成形する方法によって製造することができる。 When the low molecular p38 inhibitor of the present invention is, for example, an orally disintegrating tablet, for example, a core containing crystalline cellulose and lactose is coated with the low molecular p38 inhibitor of the present invention and, if necessary, a basic inorganic salt, A composition is obtained by coating with a water-soluble polymer-containing coating layer, and the resulting composition is coated with a polyethylene glycol-containing enteric coating layer, followed by a triethyl citrate-containing enteric coating layer, and further polyethylene glycol It can be produced by a method of coating with the containing enteric coating layer and finally coating with mannitol to obtain fine particles, mixing the obtained fine particles and additives, and molding.
上記「腸溶性被覆層」としては、例えば、セルロースアセテートフタレート(CAP)、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネート、メタアクリル酸共重合体〔例えば、オイドラギット(Eudragit) L30D−55(商品名;レーム社製)、コリコートMAE30DP(商品名;BASF社製)、ポリキッドPA30(商品名;三洋化成社製)等〕、カルボキシメチルエチルセルロース、セラック等の水系腸溶性高分子基剤;メタアクリル酸共重合体〔例えば、オイドラギットNE30D(商品名)、オイドラギットRL30D(商品名)、オイドラギットRS30D(商品名)等〕等の徐放性基剤;水溶性高分子;クエン酸トリエチル、ポリエチレングリコール、アセチル化モノグリセリド、トリアセチン、ヒマシ油等の可塑剤等の一種または二種以上混合したもの等からなる層が挙げられる。 Examples of the “enteric coating layer” include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, and a methacrylic acid copolymer [for example, Eudragit L30D-55 (trade name; Rame Co., Ltd.), Kollicoat MAE30DP (trade name; manufactured by BASF Corp.), Polykid PA30 (trade name; manufactured by Sanyo Kasei Co., Ltd.), etc.], carboxymethyl ethyl cellulose, shellac and other water-based enteric polymer bases; Sustained release bases such as coalescent [eg Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.]; water-soluble polymer; triethyl citrate, polyethylene glycol, acetylated monoglyceride And a layer composed of one or a mixture of two or more plasticizers such as triacetin and castor oil.
上記「添加剤」としては、例えば、水溶性糖アルコール(例、ソルビトール、マンニトール、マルチトール、還元澱粉糖化物、キシリトール、還元パラチノース、エリスリトール等)、結晶セルロース(例、セオラスKG 801、アビセルPH 101、アビセルPH 102、アビセルPH 301、アビセルPH 302、アビセルRC−591(結晶セルロース・カルメロースナトリウム)等)、低置換度ヒドロキシプロピルセルロース(例、LH−22、LH−32、LH−23、LH−33(信越化学(株))およびこれらの混合物等)等が挙げられ、さらに結合剤、酸味料、発泡剤、甘味剤、香料、滑沢剤、着色剤、安定化剤、賦形剤、崩壊剤等も用いられる。 Examples of the “additive” include water-soluble sugar alcohols (eg, sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (eg, Theolas KG 801, Avicel PH 101). , Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose / carmellose sodium), etc., low-substituted hydroxypropyl cellulose (eg, LH-22, LH-32, LH-23, LH) -33 (Shin-Etsu Chemical Co., Ltd.) and mixtures thereof) and the like, and further, binders, acidulants, foaming agents, sweeteners, fragrances, lubricants, colorants, stabilizers, excipients, Disintegrants are also used.
本発明の低分子p38阻害薬を有効成分とするCML治療剤の投与量は、化合物の種類、投与対象、投与ルート、CMLの重篤度等によっても異なるが、例えば、LY2228820を経口的に投与する場合、1回あたりのLY2228820量として0.5〜10mg/kg、好ましくは1〜5mg/kgを、1日3回〜5日に1回、好ましくは1日1回〜3日に1回、より好ましくは2日〜3日に1回の頻度で投与することができる。例えば「2日に1回」の頻度という場合、2日おきに投与する場合だけでなく、2日間連日投与して2日間休薬する場合も含むこととする。進行がん(固形癌)に対する第1相試験でのLY2228820の最大耐用量(MTD)は420mg、副作用と治療有効性に基づく推奨量は300mg(14日間1日2回投与後、14日間休薬のサイクル)(体重60kgとして、それぞれ14mg/kg/日及び10mg/kg/日に相当)であり、各種固形癌の移植モデルを用いた動物実験では10〜30mg/kgを1日2〜3回経口投与していることを考慮すると、後記実施例に示されるようにLY2228820、2.5mg/kgを3日に1回投与することで有意な生存期間の延長が認められたことは、意外であるとともに、患者の薬剤忍容性を考慮するときわめて有利な効果といえる。P38 MAPKはユビキタスに発現していることもあり、p38阻害薬の臨床試験(例えば、BIRB 796の関節リウマチに対する臨床試験等)では、各種の副作用が報告され、安全面での問題が指摘されているが、CMLに関しては、低用量で治療奏功性を示すので、副作用の問題を回避し得ると期待できる。 The dose of the therapeutic agent for CML containing the low-molecular-weight p38 inhibitor of the present invention as an active ingredient varies depending on the type of compound, administration subject, administration route, severity of CML, etc., but for example, LY2228820 is administered orally In this case, the amount of LY2228820 per dose is 0.5 to 10 mg / kg, preferably 1 to 5 mg / kg, 3 times a day to once every 5 days, preferably once a day to once every 3 days. More preferably, it can be administered once every 2 to 3 days. For example, the frequency of “once every two days” includes not only the case of administration every two days but also the case of administration for two consecutive days and drug withdrawal for two days. The maximum tolerated dose (MTD) of LY2228820 in the Phase 1 trial for advanced cancer (solid cancer) is 420 mg, and the recommended dose based on side effects and therapeutic efficacy is 300 mg (14 days off after 14 days of administration twice a day) Cycle (corresponding to 14 kg / kg / day and 10 mg / kg / day, respectively, assuming a body weight of 60 kg), and in animal experiments using various solid cancer transplantation models, 10-30 mg / kg 2 to 3 times a day In view of the fact that it is orally administered, it was surprising that significant increase in survival time was observed by administering LY2228820, 2.5 mg / kg once every 3 days, as shown in the Examples below. At the same time, it can be said to be a very advantageous effect considering the patient's drug tolerance. P38 MAPK may be expressed ubiquitously, and various side effects have been reported in clinical trials of p38 inhibitors (eg, clinical trials of BIRB 796 for rheumatoid arthritis), and safety issues have been pointed out. However, regarding CML, it is possible to avoid the problem of side effects because it is effective at low doses.
一方、p38に対するアンチセンス核酸、siRNA(shRNA)、リボザイム、アプタマー等の核酸性p38阻害薬をCML治療剤として使用する場合も、自体公知の方法に従って製剤化し、投与することができる。即ち、当該核酸を、単独あるいはレトロウイルスベクター、アデノウイルスベクター、アデノウイルスアソシエーテッドウイルスベクターなどの適当な哺乳動物細胞用の発現ベクターに機能可能な態様で挿入した後、常套手段に従って製剤化することができる。該核酸は、そのままで、あるいは摂取促進のための補助剤とともに、遺伝子銃やハイドロゲルカテーテルのようなカテーテルによって投与することができる。あるいは、エアロゾル化して吸入剤として気管内に局所投与することもできる。
さらに、体内動態の改良、半減期の長期化、細胞内取り込み効率の改善を目的に、前記核酸を単独またはリポソームなどの担体とともに製剤(注射剤)化し、静脈、皮下等に投与してもよい。
On the other hand, when a nucleic acid p38 inhibitor such as an antisense nucleic acid against p38, siRNA (shRNA), ribozyme, aptamer or the like is used as a CML therapeutic agent, it can be formulated and administered according to a method known per se. That is, the nucleic acid is inserted alone or in a functional manner into an appropriate expression vector for mammalian cells such as a retrovirus vector, adenovirus vector, adenovirus associated virus vector, etc., and then formulated according to conventional means. Can do. The nucleic acid can be administered as it is or together with an auxiliary agent for promoting intake by a catheter such as a gene gun or a hydrogel catheter. Alternatively, it can be aerosolized and locally administered into the trachea as an inhalant.
Furthermore, for the purpose of improving the pharmacokinetics, prolonging the half-life, and improving the efficiency of cellular uptake, the nucleic acid may be formulated (injection) alone or with a carrier such as liposome and administered intravenously, subcutaneously, etc. .
本発明の核酸性p38阻害薬は、それ自体を投与してもよいし、または適当な医薬組成物として投与してもよい。投与に用いられる医薬組成物としては、当該核酸と薬理学的に許容され得る担体、希釈剤もしくは賦形剤とを含むものであってよい。このような医薬組成物は、経口または非経口投与に適する剤形として提供される。 The nucleic acid p38 inhibitor of the present invention may be administered per se or as an appropriate pharmaceutical composition. The pharmaceutical composition used for administration may contain the nucleic acid and a pharmacologically acceptable carrier, diluent or excipient. Such pharmaceutical compositions are provided as dosage forms suitable for oral or parenteral administration.
非経口投与のための組成物としては、例えば、注射剤、坐剤等が用いられ、注射剤は静脈注射剤、皮下注射剤、皮内注射剤、筋肉注射剤、点滴注射剤等の剤形を包含しても良い。このような注射剤は、公知の方法に従って調製できる。注射剤の調製方法としては、例えば、上記本発明の核酸を通常注射剤に用いられる無菌の水性液、または油性液に溶解、懸濁または乳化することによって調製できる。注射用の水性液としては、例えば、生理食塩水、ブドウ糖やその他の補助薬を含む等張液等が用いられ、適当な溶解補助剤、例えば、アルコール(例、エタノール)、ポリアルコール(例、プロピレングリコール、ポリエチレングリコール)、非イオン界面活性剤〔例、ポリソルベート80、HCO-50(polyoxyethylene(50mol)adduct of hydrogenated castor oil)〕等と併用してもよい。油性液としては、例えば、ゴマ油、大豆油等が用いられ、溶解補助剤として安息香酸ベンジル、ベンジルアルコール等を併用してもよい。調製された注射液は、適当なアンプルに充填されることが好ましい。直腸投与に用いられる坐剤は、上記核酸を通常の坐薬用基剤に混合することによって調製されてもよい。 As a composition for parenteral administration, for example, injections, suppositories and the like are used. Injections are dosage forms such as intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like. May be included. Such an injection can be prepared according to a known method. As a method for preparing an injection, it can be prepared, for example, by dissolving, suspending or emulsifying the nucleic acid of the present invention in a sterile aqueous liquid or oily liquid usually used for injection. As an aqueous solution for injection, for example, an isotonic solution containing physiological saline, glucose and other adjuvants, and the like are used, and suitable solubilizers such as alcohol (eg, ethanol), polyalcohol (eg, Propylene glycol, polyethylene glycol), nonionic surfactants [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)] and the like may be used in combination. As the oily liquid, for example, sesame oil, soybean oil and the like are used, and benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizing agent. The prepared injection solution is preferably filled in a suitable ampoule. Suppositories used for rectal administration may be prepared by mixing the nucleic acid with a normal suppository base.
経口投与のための組成物としては、固体または液体の剤形、具体的には錠剤(糖衣錠、フィルムコーティング錠を含む)、丸剤、顆粒剤、散剤、カプセル剤(ソフトカプセル剤を含む)、シロップ剤、乳剤、懸濁剤等が挙げられる。このような組成物は公知の方法によって製造され、製剤分野において通常用いられる担体、希釈剤もしくは賦形剤を含有していても良い。錠剤用の担体、賦形剤としては、例えば、乳糖、でんぷん、蔗糖、ステアリン酸マグネシウムが用いられる。 Compositions for oral administration include solid or liquid dosage forms, specifically tablets (including dragees and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups Agents, emulsions, suspensions and the like. Such a composition is produced by a known method and may contain a carrier, a diluent or an excipient usually used in the pharmaceutical field. As the carrier and excipient for tablets, for example, lactose, starch, sucrose, and magnesium stearate are used.
上記の非経口用または経口用医薬組成物は、活性成分の投与量に適合するような投薬単位の剤形に調製されることが好都合である。このような投薬単位の剤形としては、例えば、錠剤、丸剤、カプセル剤、注射剤(アンプル)、坐剤が挙げられる。本発明の核酸性p38阻害薬は、例えば、投薬単位剤形当たり通常5〜500mg、とりわけ注射剤では5〜100mg、その他の剤形では10〜250mg含有されていることが好ましい。 The above parenteral or oral pharmaceutical compositions are conveniently prepared in dosage unit form to suit the dosage of the active ingredient. Examples of the dosage form of such a dosage unit include tablets, pills, capsules, injections (ampoules), and suppositories. The nucleic acid p38 inhibitor of the present invention is preferably contained, for example, usually 5 to 500 mg per dosage unit form, particularly 5 to 100 mg for injections and 10 to 250 mg for other dosage forms.
本発明の核酸性p38阻害薬を含有するCML治療剤の投与量は、投与対象、症状、投与ルートなどによっても異なるが、当該核酸を1回量として、通常0.01〜20mg/kg体重程度、好ましくは0.1〜10mg/kg体重程度、さらに好ましくは0.1〜5mg/kg体重程度を、1日1〜3回〜5日に1回程度、静脈注射により投与するのが好都合である。他の非経口投与および経口投与の場合もこれに準ずる量を投与することができる。 The dose of the therapeutic agent for CML containing the nucleic acid p38 inhibitor of the present invention varies depending on the subject of administration, symptoms, administration route, etc., but usually about 0.01 to 20 mg / kg body weight of the nucleic acid per dose. Preferably, about 0.1 to 10 mg / kg body weight, more preferably about 0.1 to 5 mg / kg body weight is administered by intravenous injection about 1 to 3 times a day to about once every 5 days. is there. In the case of other parenteral administration and oral administration, an equivalent amount can be administered.
本発明のp38阻害薬の投与対象となるCML患者は、特に限定されないが、望ましくは、急性転化期や移行期へと経過する前の慢性期のCML患者である。本発明のp38阻害薬はCML幹細胞の除去に特に有用であるので、該阻害薬を含有する本発明のCML治療剤は、特にイマチニブ等のTKIに対して抵抗性となったり、初期不応のCML患者、TKI治療後にCML幹細胞が残存した再発患者等に対して有効である。本明細書においては、特にことわらない限り、「TKIに対して抵抗性である」とは、治療中にTKIに対して抵抗性となった場合だけでなく、初期不応性の場合をも含む意味で用いることとする。 The CML patient to which the p38 inhibitor of the present invention is to be administered is not particularly limited, but is desirably a CML patient in the chronic phase before passing the blast crisis phase or transition phase. Since the p38 inhibitor of the present invention is particularly useful for removing CML stem cells, the CML therapeutic agent of the present invention containing the inhibitor is particularly resistant to TKI such as imatinib, or is initially refractory. It is effective for CML patients, relapsed patients with CML stem cells remaining after TKI treatment, and the like. In this specification, unless otherwise specified, “resisting to TKI” includes not only the case of becoming resistant to TKI during treatment but also the case of initial refractory. It will be used in the meaning.
イマチニブ抵抗性はBCR-ABL依存性と非依存性の機序が考えられている、前者としてはBCR-ABL遺伝子の増幅、点突然変異(例、キナーゼドメイン中のリン酸結合ループ(p-ループ)(例、G250E、Q252H、Y253F、Y253H、E255K、E255V等)、イマチニブ結合部位(例、T315I、T315A、F317L、F317V等)、活性化ループ、触媒ループ)が挙げられ、一方、後者としては、BCR-ABLシグナル下流の活性亢進、BCR-ABLに関与しないシグナル伝達経路の活性亢進、多剤耐性(MRD)タンパク質によるイマチニブの排出亢進、イマチニブ結合タンパク質(α1-酸性糖タンパク質)の増加等が挙げられる。これらのうち、キナーゼドメインの点突然変異によるものが主であると報告されているが(Cancer Cell, 2: 117-125 (2002))、本発明のp38阻害薬は、CML幹細胞を抑制できるため、変異BCR-ABL発現CMLだけでなく、いかなる機序による治療抵抗性CMLに対しても有効であり得る。 Imatinib resistance may be dependent on BCR-ABL-dependent and independent mechanisms. The former includes amplification of the BCR-ABL gene, point mutation (eg, phosphate-binding loop (p-loop in the kinase domain) ) (E.g., G250E, Q252H, Y253F, Y253H, E255K, E255V, etc.), imatinib binding sites (e.g., T315I, T315A, F317L, F317V, etc.), activation loop, catalytic loop), while the latter is , Increased activity downstream of the BCR-ABL signal, increased activity of signal transduction pathways not involved in BCR-ABL, increased discharge of imatinib by multidrug resistance (MRD) protein, increased imatinib binding protein (α1-acid glycoprotein), etc. Can be mentioned. Among these, it has been reported that the main cause is a point mutation in the kinase domain (Cancer Cell, 2: 117-125 (2002)), but the p38 inhibitor of the present invention can suppress CML stem cells. In addition to mutant BCR-ABL-expressing CML, it may be effective against treatment-resistant CML by any mechanism.
BCR-ABLの点突然変異のうち、キナーゼドメインのN末端側であるp-ループにおける変異は、急性転化期や移行期の患者に多く見られ、予後を悪化させるとの報告があるので(Blood, 102(1): 276-283 (2003))、本発明のCML治療剤は、p-ループ中に変異を有するBCR-ABL発現CMLに対する治療剤、急性転化阻止剤、予後改善剤等として、特に有用である。 Among the BCR-ABL point mutations, mutations in the p-loop, which is the N-terminal side of the kinase domain, are common in patients in the blast crisis and transition phase, and have been reported to worsen the prognosis (Blood , 102 (1): 276-283 (2003)), the CML therapeutic agent of the present invention is a therapeutic agent for BCR-ABL-expressing CML having a mutation in the p-loop, an acute transformation inhibitor, a prognosis improving agent, etc. It is particularly useful.
ABLに対する親和性がイマチニブより向上したマルチキナーゼ阻害剤であるニロチニブ、イマチニブの約260倍のABLチロシンキナーゼ阻害作用を有するダサチニブといった第2世代TKIは、多くBCR-ABL点突然変異発現細胞の増殖を抑制し得るが、イマチニブ結合部位である315番目のスレオニン残基がイソロイシンに置換されたT315I変異BCR-ABL発現細胞に対しては無効である。KW2449(Blood, 114: 1607-1617 (2009))やポナチニブ(Cancer Cell, 16: 401-412 (2009))といった第三世代マルチキナーゼ阻害薬は、T315I変異BCR-ABL発現細胞に対しても有効であることが第I相試験で示されているが、細胞遺伝学的な完全寛解に至る症例は限定的であり、T315I変異BCR-ABL発現CML細胞に対するより強力な治療薬、KW2449やポナチニブの治療効果を補完し得る併用薬の開発が望まれる。本発明のp38阻害薬は、T315I変異BCR-ABLを発現するイマチニブ抵抗性CML幹細胞に対して、単独で顕著な増殖抑制効果を示し、かつKW2449やポナチニブと併用することにより、それらマルチキナーゼ阻害剤を単独投与した場合よりも、さらにCML幹細胞の増殖を抑制し得るので、従来極めて難治性であったT315I変異BCR-ABL発現CMLに対して、本発明のp38阻害薬は特に有効な治療薬となり得る。 Second-generation TKIs such as nilotinib, a multikinase inhibitor with improved affinity for ABL, and dasatinib, which has an ABL tyrosine kinase inhibitory effect approximately 260 times that of imatinib, have proliferated many BCR-ABL point mutation-expressing cells. Although it can be suppressed, it is ineffective for cells expressing T315I mutant BCR-ABL in which the threonine residue at position 315, which is the imatinib binding site, is substituted with isoleucine. Third-generation multikinase inhibitors such as KW2449 (Blood, 114: 1607-1617 (2009)) and ponatinib (Cancer Cell, 16: 401-412 (2009)) are also effective against T315I mutant BCR-ABL expressing cells Phase I trials have shown that only a limited number of cases lead to complete cytogenetic remission, with more potent treatments for T315I mutant BCR-ABL-expressing CML cells, such as KW2449 and ponatinib. Development of concomitant drugs that can complement the therapeutic effect is desired. The p38 inhibitor of the present invention has a remarkable growth inhibitory effect on imatinib-resistant CML stem cells that express T315I mutant BCR-ABL, and when used in combination with KW2449 or ponatinib, these multikinase inhibitors The p38 inhibitor of the present invention is a particularly effective therapeutic agent for T315I mutant BCR-ABL-expressing CML, which has been extremely refractory in the past, because it can further suppress the proliferation of CML stem cells than when administered alone. obtain.
また、本発明のp38阻害薬は、がん微小環境を模倣した培養条件下で、単独投与及びTKIとの併用投与のいずれにおいても優れたCML幹細胞の増殖抑制効果を奏する。がん微小環境(ニッチ細胞)から産生される様々なシグナルは、CML幹細胞の生存及びイマチニブ抵抗性の獲得に寄与していると考えられるので、TKIやマルチキナーゼ阻害剤と併用することで、CML幹細胞でのBCR-ABLに関与しないシグナル伝達経路の活性亢進に基づくイマチニブ抵抗性CMLに対しても有効であり得る。 In addition, the p38 inhibitor of the present invention exhibits an excellent CML stem cell growth inhibitory effect both in the single administration and in combination with TKI under culture conditions that mimic the cancer microenvironment. Various signals produced from the cancer microenvironment (niche cells) are thought to contribute to the survival of CML stem cells and the acquisition of imatinib resistance. Therefore, in combination with TKI and multikinase inhibitors, CML It may also be effective against imatinib-resistant CML based on enhanced signaling pathways not involved in BCR-ABL in stem cells.
従って、本発明はまた、本発明のp38阻害薬とTKI又はマルチキナーゼ阻害薬とを組み合わせてなる、CML治療剤(併用剤)を提供する。現在承認されているチロシンキナーゼ阻害薬としてはイマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ラドチニブがあり、また、現在臨床試験中の第2世代TKIとしてバフェチニブ等がある。一方、マルチキナーゼ阻害薬としては、KW2449、ポナチニブ、AT9283等があるが、BCR-ABLに対する分子標的薬として作用するTKIとマルチキナーゼ阻害薬であれば、いかなるものであっても使用できる。 Therefore, the present invention also provides a CML therapeutic agent (combination agent) comprising a combination of the p38 inhibitor of the present invention and a TKI or multikinase inhibitor. Currently approved tyrosine kinase inhibitors include imatinib, dasatinib, nilotinib, bosutinib and radotinib, and second-generation TKIs currently in clinical trials include bafetinib. On the other hand, there are KW2449, ponatinib, AT9283, etc. as multikinase inhibitors, but any TKI and multikinase inhibitor that acts as a molecular target drug for BCR-ABL can be used.
本発明の併用剤において用いられるTKIやマルチキナーゼ阻害薬の剤形、投与経路および投与量などは、それを適用するCML患者に対して通常使用されるものであればよい。例えば、イマチニブの場合、慢性期CML患者に対しては400−600mg/日、移行期又は急性転化期の患者に対しては600−800mg/日を、1回もしくは2回に分けて経口投与することができる。ニロチニブの場合、慢性期又は移行期のCML患者に対し、1回あたり400mgを1日2回経口投与することができる。ダサチニブの場合、慢性期のCML患者に対しては1日1回100−140mg、移行期又は急性転化期の患者に対しては1回あたり70−90mgを1日2回、経口投与することができる。KW2449の場合、1日あたり50−500mgを1回もしくは2回に分けて経口投与することができる。ポナチニブの場合、1日1回45mgを経口投与することができる。 The dosage form, administration route, dosage and the like of TKI and multikinase inhibitor used in the concomitant drug of the present invention may be those normally used for CML patients to which it is applied. For example, in the case of imatinib, 400-600 mg / day is administered to patients with chronic phase CML and 600-800 mg / day is administered to patients in transitional phase or blast crisis in a single dose or in two divided doses. be able to. In the case of nilotinib, 400 mg per dose can be orally administered twice daily to CML patients in the chronic or transitional phase. In the case of dasatinib, 100-140 mg once a day for CML patients in the chronic phase and 70-90 mg once a day for patients in the transitional phase or blast crisis phase may be orally administered twice a day. it can. In the case of KW2449, 50-500 mg per day can be administered orally in 1 or 2 divided doses. In the case of ponatinib, 45 mg can be orally administered once a day.
本発明の併用剤は、TKIやマルチキナーゼ阻害薬の単独投与と比較して顕著な併用効果を奏するので、併用剤において用いられるTKIやマルチキナーゼ阻害薬の投与量は、単独投与において通常使用されている量よりも減量することができる。イマチニブやダサチニブでは血液毒性(血小板、好中球、白血球の減少等)が高頻度に発現する他、皮膚症状(皮疹等)、消化器症状(悪心、下痢等)、体液貯留(胸水貯留、眼瞼浮腫等)、肝障害、急性膵炎等の副作用が報告されており、TKIの減量によりこれらの副作用の軽減が期待される。また、マルチキナーゼ阻害薬は、BCR-ABLだけでなくAuroraキナーゼやFLT3など他のキナーゼによるシグナル伝達をも阻害するので、潜在的に副作用のリスクがが高く、実際、血栓性イベントの蓄積のため、新規診断慢性期CMLに対する第III相試験は中止となった。そのため、本発明のp38阻害薬との併用により、マルチキナーゼ阻害薬の投与量を減量できれば、副作用が低減された、より安全なCML治療剤を提供することができる。 Since the concomitant drug of the present invention has a remarkable concomitant effect compared to single administration of TKI or multikinase inhibitor, the dose of TKI or multikinase inhibitor used in the concomitant drug is usually used in single administration. The amount can be reduced from the amount. Hematological toxicity (platelet, neutrophil, leukocyte reduction, etc.) is frequently observed with imatinib and dasatinib, skin symptoms (rash, etc.), digestive symptoms (nausea, diarrhea, etc.), fluid retention (pleural effusion, eyelids) Side effects such as edema), liver damage, and acute pancreatitis have been reported. Reduction of TKI is expected to reduce these side effects. Multikinase inhibitors also block signaling by other kinases such as Aurora kinase and FLT3 as well as BCR-ABL, potentially posing a high risk of side effects and, indeed, due to the accumulation of thrombotic events The Phase III trial for newly diagnosed chronic phase CML was discontinued. Therefore, if the dose of the multikinase inhibitor can be reduced by the combined use with the p38 inhibitor of the present invention, a safer CML therapeutic agent with reduced side effects can be provided.
本発明のp38阻害薬とTKI又はマルチキナーゼ阻害薬とは、合剤として、別個に同時に、もしくは経時的に投与されてよい。但し、後述の実施例の結果より、TKI又はマルチキナーゼ阻害薬と同時もしくはTKI又はマルチキナーゼ阻害薬の投与に先だって本発明のp38阻害薬の投与を開始すると、却ってCMLの増悪を招くおそれがある。いかなる理論にも拘泥されるわけではないが、本発明のp38阻害薬はCML幹細胞を抑制するが、分化した成熟CML細胞を抑制しない可能性を否定できないため、先ずTKI又はマルチキナーゼ阻害薬の投与を開始し、成熟CML細胞をある程度抑制して病態を改善した後に、本発明のp38阻害薬の投与を開始することが好ましい。例えば、TKI又はマルチキナーゼ阻害薬投与開始から3〜14日後、好ましくは5〜10日後、より好ましくは約7日後に本発明のp38阻害薬の投与を開始することができる。 The p38 inhibitor and the TKI or multikinase inhibitor of the present invention may be administered as a combination, separately, simultaneously or over time. However, from the results of Examples described later, if administration of the p38 inhibitor of the present invention is started at the same time as TKI or multikinase inhibitor or prior to administration of TKI or multikinase inhibitor, CML may be worsened on the contrary. . Without being bound by any theory, the p38 inhibitor of the present invention suppresses CML stem cells, but it cannot be ruled out that it does not suppress differentiated mature CML cells, so first administered TKI or multikinase inhibitor It is preferable to start administration of the p38 inhibitor of the present invention after starting maturation and improving the disease state by suppressing mature CML cells to some extent. For example, the administration of the p38 inhibitor of the present invention can be started 3 to 14 days, preferably 5 to 10 days, more preferably about 7 days after the start of TKI or multikinase inhibitor administration.
以下、実施例により本発明をさらに詳しく説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in more detail, this invention is not limited to these Examples.
マウスCML幹細胞におけるp38 MAPKシグナル経路の活性化
本参考例では、テトラサイクリン誘導型CMLマウスモデルから純化したCML幹細胞を用いて、p38MAPKスレオニン180残基、並びにチロシン182残基のリン酸化状態を解析した。
Activation of p38 MAPK signaling pathway in mouse CML stem cells In this reference example, phosphorylation states of p38MAPK threonine 180 residues and tyrosine 182 residues were analyzed using CML stem cells purified from a tetracycline-induced CML mouse model.
(1)セルソーターを用いたマウス慢性骨髄性白血病(CML)幹細胞、及びマウス正常造血幹細胞の純化
(1−1)テトラサイクリン誘導型マウスCMLモデル
本CMLマウスモデルは、造血幹細胞特異的にテトラサイクリン制御性転写活性化因子(tTA)を発現するトランスジェニックマウスScl-tTAマウス (ジャクソン研究所より購入: #6209) と、tTAによって発現制御が可能なBCR-ABL1トランスジェニックマウtetO-BCR-ABL1マウス (ジャクソン研究所より購入: #6202) とを交配させたダブルトランスジェニックマウスである(Blood 113, 1613-1630 (2009))。2つトランスジーンを有するScl-tTA・tetO-BCR-ABL1マウスは、テトラサイクリン誘導体であるドキシサイクリン(Dox) (20mg/l; Sigma社製)の投与によりBCR-ABL1の発現を抑制し、Dox投与中止によりBCR-ABL1の発現を誘導することができる。このScl-tTA・tetO-BCR-ABL1ダブルトランスジェニックマウスのDox投与を中止してBCR-ABL1の発現を誘導し、5週間後、CML発症マウスを得た。
(1) Purification of mouse chronic myeloid leukemia (CML) stem cells and normal mouse hematopoietic stem cells using a cell sorter
(1-1) Tetracycline Inducible Mouse CML Model This CML mouse model is a transgenic mouse Scl-tTA mouse that expresses a tetracycline-regulated transcriptional activator (tTA) specifically in hematopoietic stem cells (purchased from Jackson Laboratory: # 6209) and a BCR-ABL1 transgenic mouse tetO-BCR-ABL1 mouse (purchased from Jackson Laboratories: # 6202) whose expression can be regulated by tTA (Blood 113, 1613- 1630 (2009)). Scl-tTA / tetO-BCR-ABL1 mice with two transgenes suppress the expression of BCR-ABL1 by administration of tetracycline derivative doxycycline (Dox) (20 mg / l; manufactured by Sigma) and discontinue Dox administration Can induce the expression of BCR-ABL1. Dox administration of this Scl-tTA · tetO-BCR-ABL1 double transgenic mouse was discontinued to induce BCR-ABL1 expression, and 5 weeks later, a CML-onset mouse was obtained.
(1−2)マウス造血幹細胞及びマウスCML幹細胞の純化
上記のごとく、CMLマウスモデルとしてScl-tTA・tetO-BCR-ABL1ダブルトランスジェニックマウスを用い、一方で、比較対照として、同腹仔のScl-tTA単独マウストランスジェニックを健常マウスとして用いた。
これらマウスのDox投与を中止し、5週間後、CML発症マウス、並びに正常マウスから骨髄単核球を取得した。この骨髄単核細胞を、抗CD4 (L3T4)、抗CD8 (53-6.7)、抗B220 (RA3-6B2)、抗TER119 (Ly-76)、抗Gr-1 (RB6-8C5)、抗Mac1 (M1/70)、抗Sca-1 (E13-161.7)、並びに抗c-Kit(2B8)抗体 (以上、BD bioscience社製)、抗CD150/SLAM (TC15-12F12.2)-Pacific blue、抗CD48 (HM48-1)-APC-Cy7抗体(以上、BioLegend社製)、抗CD135/Flk2/Flt3 (A2F10)-biotin 抗体(eBiosciences社製) 、 ストレプトアビジン-PE-Cy7 (BD Biosciences社製)を用いて染色した。これらの染色を行ったマウスCML細胞、並びに正常骨髄細胞から、セルソーター (FACS Aria III BD社製)を用いて、それぞれ、マウス長期CML幹細胞 {CD150陽性、CD135陰性、CD48陰性、cKit陽性、分化マーカー(CD4、CD8、B220、TER119、Mac1、Gr-1)陰性、Sca-1陽性細胞、(以下、「CD150+KLS細胞」と称する)}、並びに長期造血幹細胞(CD150+KLS細胞)の純化を行った。
(1-2) Purification of mouse hematopoietic stem cells and mouse CML stem cells As described above, Scl-tTA · tetO-BCR-ABL1 double transgenic mice were used as a CML mouse model, while littermate Scl- A tTA-only mouse transgenic was used as a healthy mouse.
Dox administration of these mice was discontinued, and 5 weeks later, bone marrow mononuclear cells were obtained from CML-onset mice and normal mice. These bone marrow mononuclear cells were divided into anti-CD4 (L3T4), anti-CD8 (53-6.7), anti-B220 (RA3-6B2), anti-TER119 (Ly-76), anti-Gr-1 (RB6-8C5), anti-Mac1 ( M1 / 70), anti-Sca-1 (E13-161.7), and anti-c-Kit (2B8) antibody (above, manufactured by BD bioscience), anti-CD150 / SLAM (TC15-12F12.2) -Pacific blue, anti-CD48 (HM48-1) -APC-Cy7 antibody (manufactured by BioLegend), anti-CD135 / Flk2 / Flt3 (A2F10) -biotin antibody (manufactured by eBiosciences), streptavidin-PE-Cy7 (BD Biosciences) And stained. From these stained mouse CML cells and normal bone marrow cells, using a cell sorter (FACS Aria III BD), mouse long-term CML stem cells (CD150 positive, CD135 negative, CD48 negative, cKit positive, differentiation marker, respectively) (CD4, CD8, B220, TER119, Mac1, Gr-1) negative, Sca-1 positive cells (hereinafter referred to as "CD150 + KLS cells")}, and long-term hematopoietic stem cells (CD150 + KLS cells) went.
(2)CML幹細胞におけるp38 MAPKシグナル経路の活性化
(1−2)で純化したマウスCML幹細胞、並びにマウス正常造血幹細胞を用いてp38MAPKのリン酸化状態をDuolink PLA法 (Olink社製)により解析した。p38 MAPKシグナル伝達経路の活性化を、p38 MAPKの180位のスレオニン、並びに182位のチロシンの残基のリン酸化を特異的に検出するラビット抗リン酸化p38 MAPK抗体 (Cell Signaling社製、D13E1 #8690) と、マウス抗p38 MAPK抗体 (Cell Signaling社製、28D10 #9216) の組み合わせ、また、対照として、CML幹細胞、並びに正常造血幹細胞において活性化が報告されているTGF-βシグナル経路の活性化を、Smad3の423位のセリン、並びに425位のセリンのリン酸化を特異的に検出するラビット抗リン酸化Smad3抗体 (Abcam社製、ab51451)と、マウス抗Smad3抗体(Abcam社製、ab75512)との組み合わせを、それぞれ用いて解析した。
まず、正常造血幹細胞、並びにCML幹細胞においてTGF-βシグナルの活性化を示すSmad3のリン酸化を確認した(図2下段)。次いで、p38 MAPKのリン酸化状態を解析した結果、CML幹細胞において p38 MAPKシグナル経路の活性化を示すリン酸化スレオニン180並びにチロシン182を検出した(図2左上)。従って、正常造血幹細胞とは異なり、CML幹細胞ではp38 MAPKシグナル伝達経路が活性化されていることが明らかとなった。
(2) Activation of p38 MAPK signal pathway in CML stem cells (1-2) Using mouse CML stem cells purified with mouse normal hematopoietic stem cells, the phosphorylation state of p38MAPK was analyzed by Duolink PLA method (Olink) . Rabbit anti-phosphorylated p38 MAPK antibody (D13E1 #, manufactured by Cell Signaling) that specifically detects phosphorylation of threonine at position 180 and tyrosine at position 182 of p38 MAPK. 8690) and mouse anti-p38 MAPK antibody (Cell Signaling, 28D10 # 9216), and, as a control, activation of TGF-β signaling pathway, which has been reported to be activated in CML stem cells and normal hematopoietic stem cells Rabbit anti-phosphorylated Smad3 antibody (Abcam, ab51451) that specifically detects serine at position 423 and serine at position 425 of Smad3, and mouse anti-Smad3 antibody (Abcam, ab75512) Each combination was analyzed.
First, phosphorylation of Smad3, which shows activation of TGF-β signal, was confirmed in normal hematopoietic stem cells and CML stem cells (lower panel in FIG. 2). Next, as a result of analyzing the phosphorylation state of p38 MAPK, phosphorylated threonine 180 and tyrosine 182 showing activation of the p38 MAPK signal pathway were detected in CML stem cells (upper left of FIG. 2). Therefore, it was revealed that the p38 MAPK signaling pathway was activated in CML stem cells, unlike normal hematopoietic stem cells.
インビトロでのマウスCML幹細胞に対するp38 MAPK阻害薬の抑制効果
上記のごとく、CML幹細胞においてp38 MAPK経路が活性化していることが明らかとなったため、インビトロでのp38 MAPK阻害薬によるCML幹細胞の抑制効果を解析した。
インビトロにおいてCML幹細胞の維持を解析するため、生体内でCML幹細胞を支持する微小環境を模倣したマウス間葉系細胞株OP-9細胞との共培養系を用いた。この、OP-9細胞との共培養系により、p38 MAPK阻害薬で処理したマウスCML幹細胞のコロニー形成能力を解析して、CML幹細胞の維持に及ぼすp38 MAPK阻害薬の抑制効果を解析した。
まず、マウス間葉系細胞株OP-9細胞100,000細胞を24ウェルプレートで1日間単層培養した。この細胞上に上記により純化したマウス長期CML幹細胞(CD150+KLS)細胞1,000細胞を加えた。この培養液に複数の公知のp38 MAPK阻害薬 Ly2228820 (Santacruz社より購入、最終濃度5 μM)、VX-702 (Santacruz社より購入、最終濃度5 μM)、BIRB 796 (Calbiochem社より購入、最終濃度5 μM)(各化合物の構造式を図1に示す。)を添加し、5日間、3%酸素濃度条件下、37℃で培養を行った。
これらのp38 MAPK阻害薬で処理したCML細胞を回収し、リン酸緩衝液を用いて残存する阻害薬を洗浄後、メチルセルロース半固形培地(GFM3434; Stem cell technology社製)中で、3%酸素濃度条件下、37℃で一週間培養して、コロニー形成能を評価した。
その結果、p38 MAPK阻害薬との処理によってマウス長期CML幹細胞のコロニー形成能を抑制できることが明らかとなった(図3A)。
Inhibitory effect of p38 MAPK inhibitor on mouse CML stem cells in vitro
As described above, since it was revealed that the p38 MAPK pathway was activated in CML stem cells, the suppressive effect of CML stem cells by p38 MAPK inhibitors in vitro was analyzed.
In order to analyze the maintenance of CML stem cells in vitro, a co-culture system with a mouse mesenchymal cell line OP-9 cells that mimics the microenvironment supporting CML stem cells in vivo was used. The co-culture system with OP-9 cells was used to analyze the colony-forming ability of mouse CML stem cells treated with p38 MAPK inhibitors, and the inhibitory effect of p38 MAPK inhibitors on the maintenance of CML stem cells was analyzed.
First, 100,000 cells of mouse mesenchymal cell line OP-9 cells were cultured in a monolayer in a 24-well plate for 1 day. On this cell, 1,000 mouse long-term CML stem cell (CD150 + KLS) cells purified as described above were added. Several known p38 MAPK inhibitors Ly2228820 (purchased from Santacruz, final concentration 5 μM), VX-702 (purchased from Santacruz, final concentration 5 μM), BIRB 796 (purchased from Calbiochem, final concentration) 5 μM) (the structural formula of each compound is shown in FIG. 1) was added, and the cells were cultured at 37 ° C. for 5 days under 3% oxygen concentration conditions.
CML cells treated with these p38 MAPK inhibitors were recovered, and after remaining inhibitors were washed with phosphate buffer, 3% oxygen concentration in methylcellulose semi-solid medium (GFM3434; Stem cell technology) Under the conditions, the cells were cultured at 37 ° C. for 1 week to evaluate the colony forming ability.
As a result, it was clarified that the colony-forming ability of mouse long-term CML stem cells can be suppressed by treatment with a p38 MAPK inhibitor (FIG. 3A).
インビトロでのマウスCML幹細胞に対するp38阻害剤とTKIとの併用効果
さらに、TKI抵抗性CML幹細胞に対する治療効果を検証するため、上述のp38 MAPK阻害薬 (Ly2228820、VX-702、並びにBIRB 796)、及びメシル酸イマチニブとの共処理後のCML幹細胞のコロニー形成能を解析した。
マウス間葉系細胞株OP-9細胞100,000細胞を24ウェルプレートで1日間単層培養した。このOP9間葉系細胞上に、マウス長期CML幹細胞(CD150+KLS)細胞3,000細胞を加えた。培養液に上記のp38 MAPK阻害薬Ly2228820 (5μM)、VX-702 (5μM)、及びBIRB 796 (5μM) を添加し、1日間、3%酸素濃度条件下、37℃で培養を行った。さらに、この培養液にメシル酸イマチニブ (Axon Medchem社より購入、最終濃度1μM) を添加し、4日間、(全体で5日間)、3%酸素濃度条件下、37℃で培養を行った。
p38 MAPK阻害薬とメシル酸イマチニブとの共処理を行ったCML細胞を回収し、リン酸緩衝液を用いて残存する阻害薬を洗浄後、メチルセルロース半固形培地(GFM3434; Stem cell technology社製)中で、3%酸素濃度条件下、37℃で一週間培養して、コロニー形成能を評価した。
その結果、イマチニブ存在条件下で、p38 MAPK阻害薬はマウスCML幹細胞に対する抑制効果を有することが明らかとなった(図3B)。則ち、p38 MAPK阻害剤はTKI抵抗性CML幹細胞に対して抑制効果を有していると考えられる。
Combined effect of p38 inhibitor and TKI on mouse CML stem cells in vitro, and in order to verify the therapeutic effect on TKI-resistant CML stem cells, the above-mentioned p38 MAPK inhibitors (Ly2228820, VX-702, and BIRB 796), and The ability of CML stem cells to form colonies after co-treatment with imatinib mesylate was analyzed.
The mouse mesenchymal cell line OP-9 cells, 100,000 cells, were monolayer cultured in 24-well plates for 1 day. On this OP9 mesenchymal cell, 3,000 mouse long-term CML stem cells (CD150 + KLS) cells were added. The above-mentioned p38 MAPK inhibitor Ly2228820 (5 μM), VX-702 (5 μM), and BIRB 796 (5 μM) were added to the culture solution, and cultured at 37 ° C. for 3 days under 3% oxygen concentration conditions. Furthermore, imatinib mesylate (purchased from Axon Medchem, final concentration 1 μM) was added to this culture solution, and cultured at 37 ° C. under 3% oxygen concentration conditions for 4 days (total 5 days).
CML cells co-treated with p38 MAPK inhibitor and imatinib mesylate were collected, and after remaining inhibitors were washed with phosphate buffer, methylcellulose semisolid medium (GFM3434; manufactured by Stem cell technology) Then, the colony forming ability was evaluated by culturing at 37 ° C. for 1 week under the condition of 3% oxygen concentration.
As a result, it was revealed that the p38 MAPK inhibitor has an inhibitory effect on mouse CML stem cells under the condition of imatinib (FIG. 3B). That is, it is considered that the p38 MAPK inhibitor has an inhibitory effect on TKI-resistant CML stem cells.
マウスCML幹細胞移植マウスに対するp38 MAPK阻害薬の単剤投与による治療効果
マウス生体内での、p38 MAPK阻害薬のCML幹細胞に対する治療効果を解析するため、CML幹細胞を移植してCMLを発症したマウスに対して、p38 MAPK阻害薬Ly2228820の単独投与を行い、マウスの生存期間の解析を行った。
Therapeutic effects of p38 MAPK inhibitors administered to mouse CML stem cell transplanted mice alone In order to analyze the therapeutic effects of p38 MAPK inhibitors on CML stem cells in vivo, mice transplanted with CML stem cells developed CML. In contrast, the p38 MAPK inhibitor Ly2228820 was administered alone, and the survival period of the mice was analyzed.
(1)BCRABL1-GFP遺伝子導入によるマウスCML幹細胞移植モデルの樹立
正常マウス (C57BL/6) から骨髄単核細胞を取得し、抗CD4 (L3T4)、抗CD8 (53-6.7)、抗B220 (RA3-6B2)、抗TER119 (Ly-76)、抗Gr-1 (RB6-8C5)、抗Mac1 (M1/70)、抗Sca-1 (E13-161.7)、並びに抗c-Kit (2B8)抗体を用いて染色を行った。このマウス骨髄単核細胞から、セルソーター (FACS Aria III、BD社製) を用いて、マウスの正常造血幹細胞を含む分化マーカー(CD4、CD8、 B220、TER119、Gr-1、Mac1)陰性・c-Kit陽性・Sca-1陽性細胞集団 (以下、「KLS細胞」と称する) を純化した。この細胞集団を100 ng/ml ヒトTPO (Thrombopoietin; PeproTech社製)、並びに100 ng/ml マウスSCF (Stem cell factor; 和光純薬社製) を含有する無血清培地S-Clone(SF-O3三光純薬社製)で1日間培養した。このKLS細胞に、レトロウイルスベクターを用いてBCRABL1-GFP遺伝子を導入した。1日間サイトカイン含有S-Clone培地で培養後、別途取得したマウス (C57BL/6)の骨髄単核細胞(レシピエントマウス一匹当たり5x105細胞)と共に、放射線照射 (9.0Gy) したレシピエントマウス (C57BL/6) に移植(尾静脈より注射)した (一次移植)。放射線照射は日立メディコ社製MBR-1520R-3を用い、0.5 mmアルミニウム・0.5 mm銅板で放射線にfilterをかけ、0.45から0.55 Gy/分で照射を行った。
(1) Establishment of mouse CML stem cell transplantation model by BCRABL1-GFP gene transfer Bone marrow mononuclear cells were obtained from normal mice (C57BL / 6), and anti-CD4 (L3T4), anti-CD8 (53-6.7), anti-B220 (RA3 -6B2), anti-TER119 (Ly-76), anti-Gr-1 (RB6-8C5), anti-Mac1 (M1 / 70), anti-Sca-1 (E13-161.7), and anti-c-Kit (2B8) antibodies Was used for staining. From this mouse bone marrow mononuclear cell, using a cell sorter (FACS Aria III, manufactured by BD), negative differentiation markers (CD4, CD8, B220, TER119, Gr-1, Mac1) including mouse normal hematopoietic stem cells are negative. Kit positive and Sca-1 positive cell populations (hereinafter referred to as “KLS cells”) were purified. This cell population was divided into 100 ng / ml human TPO (Thrombopoietin; manufactured by PeproTech) and 100 ng / ml mouse SCF (Stem cell factor; manufactured by Wako Pure Chemical Industries), serum-free medium S-Clone (SF-O3 And cultured for 1 day. BCRABL1-GFP gene was introduced into the KLS cells using a retroviral vector. Recipient mice (9.0Gy) irradiated (9.0Gy) with bone marrow mononuclear cells (5x10 5 cells per recipient mouse) of mice (C57BL / 6) obtained separately after culturing in cytokine-containing S-Clone medium for 1 day C57BL / 6) was transplanted (injected from the tail vein) (primary transplantation). For radiation irradiation, MBR-1520R-3 manufactured by Hitachi Medical Corporation was used, and the radiation was filtered with a 0.5 mm aluminum / 0.5 mm copper plate and irradiated at 0.45 to 0.55 Gy / min.
(2)CML幹細胞移植マウスに対するp38 MAPK阻害薬の治療効果
BCR-ABL1-GFP遺伝子を導入した造血幹細胞を移植してCMLを発症したマウスに対して、移植8日後から50日後まで、コントロール投与(人工胃液;900 ml二回蒸留水、 2.0 g NaCl、 7 ml conc. HCl、 3.2 g pepsin含有)、またはLy2228820 (25 mg/ml DMSO溶液を上記の人工胃液で1/100希釈して調製。最終濃度0.25 mg/ml)を含む200 μl人工胃液を、Ly2228820を最終濃度2.5 mg/kgで、3日毎に経口投与した。これらCML発症マウスの生存期間を解析した。
その結果、Ly2228820の投与群では、コントロール群と比較して、CMLの発症を改善した(図4)。従って、p38 MAPK阻害薬はインビボにおいてCML幹細胞に対する治療効果を有していると考えられる。
(2) Therapeutic effect of p38 MAPK inhibitor on CML stem cell transplanted mice
Control administration (artificial gastric juice: 900 ml double-distilled water, 2.0 g NaCl, 7 days after transplantation from 8 to 50 days after transplantation of hematopoietic stem cells introduced with the BCR-ABL1-GFP gene) HCl, 3.2 g pepsin) or Ly2228820 (prepared by diluting 1/100 of the 25 mg / ml DMSO solution with the above artificial gastric juice. Final concentration 0.25 mg / ml) Was orally administered every 3 days at a final concentration of 2.5 mg / kg. The survival period of these CML mice was analyzed.
As a result, the onset of CML was improved in the Ly2228820 administration group compared to the control group (FIG. 4). Therefore, p38 MAPK inhibitor is considered to have a therapeutic effect on CML stem cells in vivo.
誘導型CMLマウスに対するp38 MAPK阻害薬とダサチニブとの併用効果
(1)投与プロトコル1(Ly2228820同時投与開始、連日投与)
参考例1で用いた誘導型CMLマウスモデルを用いて、ダサチニブの単独投与、並びにp38 MAPK阻害剤とダサチニブの併用投与による治療効果の評価を行った。
上記のScl-tTA・tetO-BCR-ABl1ダブルトランスジェニックマウスを用い、ドキシサイクリン投与中止して、0日目から30日後まで、ダサチニブ(商品名スプリセル、5 mg/kg/日、ブリストルマイヤーズ社製)の経口投与を行った。このスプリセル投与マウスを2群に分け、1群には200 μlの人工胃液 (900 ml二回蒸留水、2.0 g NaCl、 7 ml conc. HCl、 3.2 g pepsin含有)、もう1群にはLy2228820 (0.25 mg/ml)を含む200 μl人工胃液を、Ly2228820最終濃度2.5 mg/kg/日で、CML誘導後0日目から30日まで連日経口投与した。
その結果、ダサチニブ単独投与群と比較して、ダサチニブとLy2228820の併用投与群ではCML誘導マウスの明らかな延命効果は見られなかった(図5)。
Combined effect of p38 MAPK inhibitor and dasatinib on induced CML mice
(1) Administration protocol 1 (Ly2228820 simultaneous administration, daily administration)
The induced CML mouse model used in Reference Example 1 was used to evaluate the therapeutic effects of dasatinib alone and the combined administration of p38 MAPK inhibitor and dasatinib.
Using the above Scl-tTA / tetO-BCR-ABl1 double transgenic mouse, doxycycline administration was discontinued, and from day 0 to 30 days, dasatinib (trade name Spricel, 5 mg / kg / day, manufactured by Bristol Myers) Was administered orally. The Splicel-administered mice were divided into two groups, one group containing 200 μl of artificial gastric juice (containing 900 ml double-distilled water, 2.0 g NaCl, 7 ml conc. HCl, 3.2 g pepsin), and the other group Ly2228820 ( 200 μl artificial gastric fluid containing 0.25 mg / ml) was orally administered daily from day 0 to day 30 after CML induction at a final concentration of Ly2228820 of 2.5 mg / kg / day.
As a result, as compared with the dasatinib alone administration group, the dasatinib and Ly2228820 combination administration group did not show a clear life-prolonging effect of CML-induced mice (FIG. 5).
(2)投与プロトコル2(Ly2228820 1週間後投与開始、2-3日おきに投与)
p38 MAPKはユビキタスで発現していることもあり、p38 MAPK阻害薬の各種臨床試験においても多くの副作用が報告されていることから、p38 MAPK阻害薬を連日投与から2日(n=15)又は3日(n=16)に1回投与に、投与間隔をあけてみた。また、p38阻害薬のCML幹細胞に対する抑制効果は実証されたが、分化した成熟CML細胞に対する反応は明らかでないため、まずダサチニブでCML細胞をある程度死滅させた後でp38 MAPK阻害薬を作用させるべく、ダサチニブ投与開始から1週間後に、Ly2228820の投与を開始した。
その結果、ダサチニブ単独投与群と比較して、ダサチニブとLy2228820の併用投与群ではCML誘導マウスの生存率を改善することが明らかとなった(図6)。則ち、p38 MAPK阻害剤との併用により、ダサチニブ抵抗性のCML幹細胞の治療効果を高められることができ、CMLの発症を抑制できることが期待される。
(2) Administration protocol 2 (Ly2228820 administration started 1 week later, administration every 2-3 days)
Since p38 MAPK is expressed in ubiquitous, and many side effects have been reported in various clinical trials of p38 MAPK inhibitors, p38 MAPK inhibitors were administered 2 days after daily administration (n = 15) or The administration interval was tried once every 3 days (n = 16). In addition, although the suppressive effect on CML stem cells of p38 inhibitors has been demonstrated, since the response to differentiated mature CML cells is not clear, first kill CML cells to some extent with dasatinib and then act on p38 MAPK inhibitors Administration of Ly2228820 was started one week after the start of dasatinib administration.
As a result, it became clear that the survival rate of CML-induced mice was improved in the dasatinib and Ly2228820 combination administration group compared to the dasatinib alone administration group (FIG. 6). In other words, combined use with a p38 MAPK inhibitor is expected to increase the therapeutic effect of dasatinib-resistant CML stem cells and suppress the onset of CML.
インビトロでのヒトCML幹細胞に対するp38 MAPK阻害薬の抑制効果
ダサチニブ抵抗性のヒトCML幹細胞に対するp38 MAPK阻害薬の治療効果を評価するため、マウス間葉系細胞株OP-9細胞上でCML患者由来のヒトCML幹細胞の共培養を実施した。
まず、マウス間葉系細胞株OP-9細胞100,000細胞を24ウェルプレートで1日間単層培養した。この細胞上にヒトCML幹細胞6,000細胞(ダサチニブで処理しないウェル)または100,000細胞(ダサチニブで処理するウェル)を加えた。この培養液に最終濃度5 μMでLy2228820を添加し、1日間5%酸素濃度条件下、37℃で培養した。この培養液に最終濃度500nMでダサチニブ、を添加し、2日間5%酸素濃度条件下、37℃で培養した(全体で3日間)。細胞を回収し、リン酸緩衝液を用いて残存する阻害剤を洗浄後、メチルセルロース半固形培地(GF+H 4435; Stem cell technology社製)中で、5%酸素濃度条件下、37℃で一週間培養して、コロニー形成能を評価した。
その結果、p38 MAPK阻害薬は、ヒトCML患者由来のCML幹細胞に対して抑制効果を示した(図7左(コントロール))。また、ダサチニブとp38 MAPK阻害薬との併用は、ダサチニブの単独投与に比べてコロニー形成能をさらに抑制した(図7右(ダサチニブ))。則ち、p38 MAPK阻害薬はTKI抵抗性のヒトCML幹細胞に対して抑制効果を有していると考えられる。従って、p38 MAPK阻害薬はCML患者のヒトCML幹細胞に対する治療薬となる可能性がある。
Inhibitory effect of p38 MAPK inhibitor on human CML stem cells in vitro In order to evaluate the therapeutic effect of p38 MAPK inhibitor on dasatinib-resistant human CML stem cells, it was derived from CML patients on mouse mesenchymal cell line OP-9 cells Co-culture of human CML stem cells was performed.
First, 100,000 cells of mouse mesenchymal cell line OP-9 cells were cultured in a monolayer in a 24-well plate for 1 day. On this cell, 6,000 human CML stem cells (well not treated with dasatinib) or 100,000 cells (well treated with dasatinib) were added. Ly2228820 was added to this culture solution at a final concentration of 5 μM, and cultured at 37 ° C. under 5% oxygen concentration conditions for 1 day. Dasatinib was added to this culture solution at a final concentration of 500 nM, and cultured at 37 ° C. under 5% oxygen concentration conditions for 2 days (3 days in total). After recovering the cells and washing away the remaining inhibitor with phosphate buffer, in a methylcellulose semi-solid medium (GF + H 4435; manufactured by Stem cell technology), the cells were isolated at 37 ° C under 5% oxygen concentration. After culturing for a week, colony forming ability was evaluated.
As a result, the p38 MAPK inhibitor showed an inhibitory effect on CML stem cells derived from human CML patients (FIG. 7 left (control)). Moreover, the combined use of dasatinib and a p38 MAPK inhibitor further suppressed the colony-forming ability as compared to dasatinib alone (FIG. 7, right (dasatinib)). In other words, p38 MAPK inhibitors are thought to have an inhibitory effect on TKI-resistant human CML stem cells. Therefore, p38 MAPK inhibitors may be therapeutic agents for human CML stem cells in CML patients.
TKI治療によれば根絶を免れる可能性のあるCML幹細胞(特にT315I変異BCR-ABL発現CML幹細胞を含むTKI抵抗性CML幹細胞)を、効率よく排除することができる。またTKIやマルチキナーゼ阻害薬との併用により、より治療奏功性を高めることができ、CMLとPh+ALLの再発の予防効果をもたらすとともに、TKIやマルチキナーゼ阻害薬の投与量を低減することができ、副作用を軽減させる点で有用。さらに、これまで有効な治療方法の確立されていない再発CML患者に対する新たな治療方法となる。 According to the TKI treatment, CML stem cells (particularly TKI-resistant CML stem cells including T315I mutant BCR-ABL-expressing CML stem cells) that can escape eradication can be efficiently eliminated. In addition, combined use with TKI and multi-kinase inhibitors can improve the response to treatment, prevent relapse of CML and Ph + ALL, and reduce the dose of TKI and multi-kinase inhibitors Can be useful in reducing side effects. Furthermore, this is a new treatment method for recurrent CML patients for which no effective treatment method has been established so far.
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